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A

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 Doctor Sachin Panda. Doctor Sachin 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 hours 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, Doctor 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, doctor Panda and I discuss how our circadian behaviors, everything from when we wake up, to when we view light, to when we avoid viewing light, to when we eat and what we eat and when we socialize and how we socialize, impacts our biology and our psychology and how all of that has a strong impact on our health. During today's discussion, you will learn how restricting your feeding to specific periods within each 24 hours cycle, or perhaps even exploring longer patterns of fasting and eating cycles, can impact everything from the health of your liver to your gut to your brain, and how all of that impacts things like mood and your ability to perform cognitive work. Indeed, today's discussion goes deep into all aspects of intermittent fasting, aka time restricted feeding. We talk about the basic science as well as the recent clinical trials that have explored time restricted feeding in a diverse range of people, including men, women, children, people with diabetes, people who are otherwise healthy, and much, much more. I'm quite aware that intermittent fasting is a topic of much debate these days. We go deep into that debate and by the end of today's discussion, you can be certain that you will have learned all the latest and all the details, all made very clear to you thanks to the incredible expertise, discovery and clear communication of Doctor Panda. As some of you may already know, Doctor 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 Doctor 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 element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium and potassium, the so called electrolytes, and no sugar. Now, salt, magnesium and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science backed electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drinkelement. That's lmnt.com huberman to claim a free element sample pack with your purchase. Again, that's drinklimentlmnt.com hubermandhenne and now for my discussion with doctor Sachin Panda. Sachin Doctor Panda, so good to see you again.

B

Yeah, good to see you.

A

We are colleagues still, but we used to be right across the street from one another in 28.

B

Yeah, I remember those days. Yeah.

A

Yeah. So I'm delighted that you're here. I think we're going to talk about a number of things, mainly intermittent fasting time, restricted feeding and health, but also the many other things that you're doing. Just before we started recording, we were discussing your recent paper in nature that involved recordings from postmortem human retina. So maybe if there's time at the end, we can get back to your lab has shown that it can essentially maintain or resurrect neurons from dead people in order to potentially and eventually provide transplants to rescue vision in the blind. So that's extremely exciting, but, of course, not the main focus of today's discussion. So we'll have to split it up. The first question I have is, how am I supposed to define fasting and time restricted feeding? Meaning when I go to sleep every night, I'm not eating. So in some sense, everybody is doing time restricted feeding to some degree or another. At what point can we start thinking about a pattern of eating? Is time restricted feeding so called intermittent fasting? Does it have to do with how regular one is about the start and stop times? How do you think about defining intermittent fasting? Time restrictive 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?

B

Well, you know that intermittent fasting covers many types of fasting. Actually, it started a long time ago, and it's embedded into the history of caloric restriction. Almost 100 years ago, people showed that if you reduce calorie intake in a rat, then that rat can live for a long time. And in those experiments, the calories were reduced every single day. And that led to the idea that if we cut down our calories by 20%, say, then we can potentially live longer by doing two things. One is preventing age related disease. Or even if we fall sick, maybe we can accelerate, cure, and keep the repair mechanism going so that we can live longer. But it was very difficult to count calories every day and reduce, maintain that. I must say that it's not that calorie restriction is impossible or we are not doing it. In fact, a lot of us, we do count calories in our subconscious mind. Every time you take out, we take out a soda bottle or something, I'm looking at, okay, 160 kilo calories. 30 kilo calories. Zero kilo calories. We are doing that. So the point is, we are doing, subconsciously, some kind of calorie 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. And in fact, this every other day feeding also led to very similar, almost equivalent health improvement as continuous calorie restriction. So then the idea was, well, every other day is a little bit hard for humans, but just imagine, I would just get to eat only one day and then another day. Then the idea came, well, for humans, can they eat less for one or two days in a week? So that led to this five two diet where people can eat for five days and then two days, they have to reduce calories. So that's also intermittently people are fasting. 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, three months, you can fast or reduce calorie. And he also found many benefits of calorie restriction.

A

Was there were those studies on humans.

B

Many of the studies started in mice, but alternate day fasting, five two and walters periodic fasting, all of them have now been done in humans. Not for longevity, of course, because you cannot do those for a long time, but for weight maintenance, for reducing some signs of aging or reversing, those things have been done. So all of them have been done in humans, mostly healthy humans, and in some cases, people with pre diabetes or some aspects of metabolic disease. So that led to the idea 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 umbrella term became intermittent fasting. So if you look up the scientific literature, most intermittent fasting involves intentionally reducing calories for at least one or two days in a week or few days in a month. So when we publish time restricted feeding, the initial mouse experiments, and even now, most of the mouse experiments, we want to test what is the impact of time restriction versus calorie restriction. So, in these experiments, we don't reduce calorie on any day of mouse life. So the mice ate the same number of calories as the ad libitum fed mice. But still they see health benefit. So that's why we call it time restricted feeding. But since it involves living without food for several hours for some people, which can be very difficult, the initial experiments was done. They were done for 8 hours of feeding and 16 hours of fasting. That kind of became popular. And so that's why people use the same term as intermittent fasting. And now, if you say intermittent fasting in popular literature or popular media, then people usually refer to time restricted eating. So now coming back to, how do you define time restricted feeding? So, the way we have been trying to define experimentally and also in literature is trying to confine all your energy intake from solid and liquid food combined within a consistent window of eight to 12 hours. Because that's something that doable. Of course, people have done time restrictive feeding with 4 hours, 6 hours. And some people even try to eat everything within 2 hours, one meal a day. But the point is, those are not feasible to maintain for a very long time for a lot of people.

A

One question about the six hour versus eight hour versus twelve hour feeding window. Is it important that the feeding window begin and end at the same time? 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, usually some caffeine and electrolytes in the period before my first meal. And my first meal always lands sometime between 11:00 a.m. and twelve noon. There are exceptions. Occasionally I'll have a breakfast, 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, eight, eight thirty, nine pm. That's what works for me. Is that consistency affording me any benefit? And let's just leave aside total caloric number, macronutrients, plant based meat, et cetera. 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?

B

Yeah. So the start of the feeding window, that's interesting, because the concept of time restricted feeding, when I describe animal studies, it's feeding for humans, it's eating. So the concept actually came from the science of circadian rhythm. So that means our body has an internal timetable that's present in every cell, in every organization, that pre programs many molecular aspects of the cells that leads to physiology and all that stuff. So that essentially there is a predetermined timetable for every cell, every organ, to do certain things at certain time. And the circadian clocks, as you and I know, are more sensitive to light. Light is the most dominant time giver. So, for example, when daylight saving time changes or when we travel from one time zone to another time zone, we feel kind of crappy because our daily activities are out of sync from our internal clock. So that was known for a very long time. But then around the year 2000, 2002, there was a famous experiment by Uli Sibler from Switzerland. What he did, he just fed the mice at the wrong time. Mice are nocturnal, they're night feeders. And when he fed 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 clot. And subsequently the same experiment has been repeated many times. And we repeated that in 2009 and we figured out, yes, actually outside this brain center called suprachiasmatic nucleus, or SCN, which is considered the master circadian clock. Almost the rest of the brain even follows when we eat. And that came out from pure Chambon's lab in Europe, where they systematically looked at even places that are very close to the Asian for those who are, who know, dorsal medial hypothalamus or paraventricular nucleus, all of this within a couple of four or 5 SCN. But they were following food queue.

A

Amazing.

B

So then, now if we think about it, so for example, when the daylight saving time changes, just 1 hour change or 1 hour change in alignment between our internal time and external time leads to kind of feeling groggy and feeling not at a peak for four months, for one or two days. So the rule of thumb is when I, 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, you're moving through three time zones, then on an average it will take three days to catch up with the New York Times. For some people it can be even slower, and for some people it can be two days. But the bottom line is, yes, there is a desynchrony. So then what does it mean for the body? So one of the function of clock is to anticipate when you're going to wake up, for example, so the blood pressure slightly goes up or heart rate goes up, our breathing goes up. Similarly for food, almost every organ that is involved in feeding or eating, digestion, all of them have clocks. So even from saliva production, that is the first phase of digestion, to secretion of all the digestive juice in the stomach, and then absorption of nutrient, then liver metabolism. Everything the whole village expects when you're supposed to eat and they're getting ready for you to eat the first meal after fasting for a long time. So that's why it's breaking the fast or breakfast. And when that time changes, when you change it by two or 3 hours from one day to another, then sometimes they're like, oh, food didn't come, maybe we'll come at a wrong time, we were at the wrong time. And then they'll track the new eating times. So suppose one day you have been eating every day at 08:00 a.m. i ate at 08:00 a.m. is that when.

A

You start your feeding window? When does your feeding window shut?

B

06:00 p.m. so I eat for around 10 hours.

A

Okay.

B

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 eight, but it arrived at ten. Maybe tomorrow the food will arrive somewhere between eight and ten, so we'll be ready around nine. I see. Next day, if I come back and eat at 08:00 then I may eat, but my clock is not ready to digest that food. So that's why this idea is, you have to be consistent to take advantage of this anticipatory activity of our clock in different systems to get the best out of it.

A

Is there evidence that those anticipatory systems, as they relate to digestion, help us better assimilate our food? I would imagine so. I mean, if you have the gastric juice 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?

B

The anticipatory signal is really important even from waking up. The reason why many people feel not ready completely when they wake up to an alarm clock, 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 daylight saving time changes, particularly when we have to wake up 1 hour early. What happens? People who have underlying heart condition when they are waking up, when the body is not ready or heart is not ready, and all of a sudden the heart has to start pumping a little bit harder, then there is chance of heart attack. And in fact, people have looked at hospital records and they find that on those days there is a sharpen rise.

A

In heart attacks and car accidents, and.

B

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

A

Yeah, I've experienced that where if I've worked late or I couldn't eat dinner or something, and then I get home, I always debate whether or not to try and sleep. But if I'm too hungry, oftentimes it's challenging. And so, for me, sometimes consuming something that at least seems easily digestible, like yogurt or something in a liquid form, is better for me than if I eat a meal. I've made the mistake of going to the refrigerator, being super hungry and eating a bunch of food at ten 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 cognitively weighed down. So I think what you just described makes a lot of sense. So if someone were to select a feeding window, regardless of whether or not it falls into classic intermittent fasting, time restricted feeding sounds like eating your first bite of food and eating your last bite of food at more or less the same time each day has benefits. I have this question. You mentioned feeding versus eating, and I think it's actually not just a grammatical semantic issue. And here's why. We tend to think about when you take your first bite of food and then when you take your last bite of food. Course foods digest at different rates. More fat in there is going to digest, make carbohydrates digest slower, et cetera. I mean, there's all these adjustments to the glycemic index and so forth. With foods in combination, is it better to think about not eating, but your fed state and blood sugar? So, for instance, I often get asked on social media, does blank break a fast so and so? I like to think about it scientifically, like, okay, does plain water break a fast? No. Does air break a fast? No. Does one grain of sugar of sucrose break a fast? Well, probably not. But does one teaspoon of sugar break a fast? Well, you could say yes, but transiently, 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 a rise in blood glucose that cannot be reversed? In other words, if I'm going to eat my first meal every day at noon, and I'm going to eat my last bite of food at 08:00 p.m. and at 09:00 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 if I went for a hard run that morning, maybe by 09:30 a.m. i'm back in a quote unquote fasted state. So what is the fasted state really? Because when I'm eating at 08:00 p.m. just to give another example, I start fasting at 08:01 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 detail, but I think a lot of the confusion out there about what breaks a fast is related specifically to this issue, which is if I eat a whole pizza after sitting around all day, it's very different than if I eat a whole pizza after having run a 26 miles marathon that day. Very different, metabolically speaking. So how should people think about fasted versus fed? Can we be mildly fasted versus severe fasted? Can we be fed ish versus very fed? Anyway, I'll stop asking questions now because they all relate to the same theme.

B

Yeah. Now these are very interesting question. And then, unfortunately, as you can, as you might have seen in life, the most obvious questions are often unanswered because it's so hard to do these damn experiments. Because if you really want to address this in humans, you have to bring humans, put them in isolation, just like you said. I can now imagine planning five or six different experiments. Each experiment should involve eight or ten volunteers, each gender, sex, and then do it. So it's difficult. So now let's go back to seed. How do we. Let's dissect it in terms of, say, indirect calorimetry. So, for example, indirect calorimetry is based on this principle that whatever oxygen we breathe in and carbon dioxide we breathe out. If we can measure these two, then we can figure out whether our body in total, we are not saying whether it's the liver, gut, or fat or muscle in total, whether it's consuming glucose or fat as energy source. The idea is when we fast, when we are without food for several hours, then ideally our body will tap onto glycogen first, and then do a little bit of fat. And then when the body is mostly running on fat, then that ratio of CO2 to oxygen will come to 0.7. But what is interesting is we can do these experiments in mice. So we can go to mice and ask, okay, so what happens in mice? So, in mice, mice are a little bit very different, because mice are not simply little people. The metabolism is different. They store relatively less glycogen than humans do in terms of total metabolism. So they overnight. Within twelve to 14 hours, the RER respiratory exchange ratio, or this ratio will go from one. When they are consuming mostly glucose or carbohydrate as energy source, it will slow down slowly go to 0.70.75. So after twelve to 14 hours, they are kind of mostly running on fat. So now, as we give them food, within ten or 15 minutes, they're not actually consuming a couple of grams of food. They might have consumed, say, 100 or 200 milligrams of that chow, so, which is less than, say, 5% of the food. And then the RER will immediately begin to rise as if that small amount of food stopped that fat burning process and cranked up the carbohydrate burning process.

A

When you say fat burning process, you mean body fat stores being burned, right? Not dietary fat, correct.

B

Yeah. So it's all body fat means. That's why I said we don't know where that fat is being burned, because we're just measuring how much mice is breathing in and out. So, for example, it can be from the skin. So subcutaneous fat or belly fat, but not dietary fat? No. By that time, the dietary fat is already observed 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.

A

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

B

So here in this case, for example, for mice, we know that as soon as they start eating, the RER goes up. Coming back to your question, what would be ideal for us to do? The experiment would be, okay, so we'll go back to that and then give the mouse maybe 100 milligrams of food and mouse runs around in the kids, 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 see. Let's stay on this and then I'll come back and talk about non caloric food and whether that is considered.

A

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B

So there is a famous experiment that was published last year by Jota Kahasi's lab, and it came out in science, and that relates to caloric restriction. And we kind of started with this idea. We started discussion that the rat experiments were done with caloric restriction, and researchers gave reduced calorie consumption by 20% or 30% and get that food, the rats, and then subsequently mice, and they all lived longer. What is interesting is, in all those experiments, the researchers came and gave this bolus of food at one time. Whereas the ad libitum fed mice or rats, they had access to food all the time. So they were eating all the time. And then these rats were given 20% less. And what happens is, these mice or rats, they're not going to take that less food, which is rest on now and just eat a little bit of lunch, and then snack after 3 hours, or snack after 3 hours. They gobble up all that food. Within two to 3 hours. Maximum 4 hours, food is gone.

A

So they're sort of on the Omad diet, the one meal a day.

B

Yeah, they're almost like in one meal a day, three to 4 hours, food is gone. Or you can sit there on 4 hours eating or feeding and 20 hours fasting. So then the question became, well, the benefit of calorie 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 three 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 ten or 15 different small portions and then give them to mice in every 2 hours. So Joe Takahashi, who actually published the first paper in 2017 showing that most caloric restrictions, I mean, he used the protocol that was used by caloric restriction field, it actually creates a condition of time restriction. So he showed that, and then he went back and worked with engineers to come up with a smart kids where he could actually tell, he could program how much food is given to mice at what time of the day or night, completely programmed. So then he took this, for example. Suppose the ad libitum fed mice eats 5 grams of chow in a day. And if you want to reduce calories by 20%, then the Sierra mouse should get 4 grams of food. And it divided this into nine or ten meals and then gave them in every 90 minutes. So in this case, they're 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 getting some food. And then he measured how long the mouse is going to live, and he used. This is a very standard protocol. People count how many mice are dying on which day and then examine them to see whether they died because there was an accident or they actually, there was a natural cause. And then they calculate at the end, what is the half life. So 50% survival, because that's, on an average, that's a good indicator, because if there is an outlier that will live for a long time, then that can skew. So what was interesting was the ad libitum fed mice. Of course, they lived certain number of days. And then these caloric restricted mice that never got into super fasting, but kind of eating snacking throughout day and night, that also live 10% extra, 10% longer. So that means caloric restriction, extended lifespan by 10%.

A

I wonder about this, because recently there were a bunch of news headlines about intermittent fasting, and frankly, I was frustrated. If you looked at one major news outlet, they would say time restricted feeding affords no additional benefit beyond caloric restriction for weight loss. Then another popular press venue, let's call it that same study described as time restricted feeding doesn't work. And then another one, maybe someplace even more extreme, time restricted feeding only beneficial because of caloric restriction or something like that. So what you've essentially got are three different interpretations of the same data, all of which are, well, two of which are true, one of which is false, in my opinion. But what I think people take away from that is, oh, time restricted feeding isn't valuable, which is not the case. I think, for many people, it's a convenient way to eat, because, at least for people like me, it's simpler to designate between portions of my day when I'm eating and portions of my day when I'm not eating, as opposed to portion control. For other people, portion control can work, but all of that is related to either maintenance or loss of weight. None of it deals with the potential health benefits independent of weight loss. I think that if we can segment those out, obviously in humans, it's hard to know if a given treatment or experiment is extending life, because you don't really know how long people would live anyway, whereas with mice, you have some sense of when the mortality was likely to occur. So what can we say about time restricted feeding and longevity in terms of biomarkers or in terms of any other indications that people who start and stop their feeding window at a consistent time, somewhere between eight and 12 hours per 24 hours cycle, are tilting the scales towards living longer as opposed to living shorter.

B

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

A

So 20%.

B

20%.

A

Okay, so let me make sure I understand. So that I make sure I understand. If you take a certain number of calories and you distribute them throughout the 24 hours cycle.

B

Yeah.

A

It's caloric restriction. The mice will live 10% longer if you, however, restrict that to the active cycle. So for humans, the daytime, then 20%, then they live 20% longer.

B

20% longer.

A

So it's not just total caloric intake.

B

Yeah.

A

Meaning it's not just important to be sub maintenance and calories for sake of longevity. It also is important as to when in the 24 hours cycle you eat those calories. Do I have that right?

B

So now that's still the story is not over because these mice are fed during daytime when they're not supposed to eat.

A

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.

B

But when a fed mice during nighttime, 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 lived 35% longer than they control.

A

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

B

Yeah, so it's around 80. It used to be 80, now slowed, reduced a little bit because of COVID but let's take 80.

A

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

B

Yeah, yeah, yeah. So that 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, a one C equivalent, or glucose control, cholesterol, all this stuff. He could not find anything that predicted the benefit of caloric restriction. So that means in this experiment, whatever we know so far, the predictor of longevity, none of them could predict whether this CR only mouse, which ate throughout day and night, that mouse is going to live less than the night fed mouse that was going to live 25% extra.

A

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

B

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

A

Body composition across all these different groups.

B

Across all these groups.

A

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

B

Taking a snapshot of that. And then another thing with the human study that we are referring to here, 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 14 hours. All participants had to reduce their caloric intake and they reduced by almost 25%. The CR group continued with ten hour sitting window, and the cross time restricted group had to eat the same number of calories within 8 hours.

A

So it's just a two hour difference.

B

It's just a 2 hours difference.

A

Okay? So that people, I just want to make sure people can understand. So, in this human study, which is the one that I felt that the popular press venues, all except one venue, got either semi wrong or badly wrong in terms of their conclusion. That was my interpretation anyway, was that either people came into the study eating basically in a ten 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 ten to twelve hour feeding window anyway. So you're saying they either did caloric restriction portion control within the ten 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 eight hour feeding window and they didn't see any difference in terms of weight loss. Yeah, but it's not all that surprising, right? I mean, if it's just a two hour difference.

B

Yeah, exactly. So we have done that experiment in mice and we don't see difference in not only weight loss, many other markers. And I was telling you about this, Joe Takahashi's paper, wherever I told you that he allowed these mice to eat within 2 hours or 12 hours sub caloric diet.

A

Two or twelve. Two or twelve, yeah, that's dramatic.

B

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

A

Can we conclude for humans that whether or not a feeding window is 4 hours, 6 hours, 8 hours or twelve doesn't matter, provided the calories are similar or same?

B

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

A

But that should be changing, right? Because the NIH, I know this because I'm on study section, which is just a bunch of people who review grants, is that every grant now has to include sex as a biological variable. It's hard to get away with, or 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, especially if there are differences.

B

So in this case there are many. There was also another paper in time restricted feeding that also came out a big paper showing that the thermogenesis was accounting for loss in fat mass in time restricted fed mice. That was also done only in male mice. So this is, 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.

A

Reduce their calorie intake just because of gut volume. I tried one meal per day, and I felt like I was eating so much at that one sitting that it led to a lot of gastric distress, and I got 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.

B

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

A

Relative energy deficit in sports. Okay.

B

Yeah. Because nearly 40% of athletes, not the NFL guys, but there are a lot of people who do track and field, and nearly 40% of athletes actually experience this. Reds, red s. Without knowing, can male.

A

And female athletes both experience reds? So it's reds. R e D s. Relative 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 so males and females can experience it. So in females, I've heard that Reds can lead to amenorrhea. So loss of the menstrual cycle.

B

Yeah. So that's 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, then they will lose their menstrual cycle, which may be common, but it's not normal or optimum for health.

A

And even if they don't want to get pregnant. Yeah, yeah, yeah, yeah. We had an expert on female hormones come on and say the very same thing, that regular cycling is very important of ovulatory menstrual cycle is important to try and maintain.

B

Yeah. So that's one. But then what is really concerning is it does affect bone health. And in this state, people actually, over a long period of time, they lose bone mass and the bone also becomes more prone to injury, micro fracture and fractures. 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 means. The reason why these women are losing menstrual cycle is the HPG axis is disrupted. Hypothalamus, pituitary, gonadal axis. And it starts. It may start even 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 rets is also depression, anxiety, bipolar like symptoms. And we know that many, many athletes experience that. We think that, well, 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 attempt at suicide or suicide. So this is a serious issue. And there's also another new topic in the lab to come up with a mouse model of redskin and then study it. But this is one risk why we should not reduce our eating interval to one meal or very short time, because it can have adverse side effect that we don't know now. 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 unhealthy individuals, and they were in the studies. So the study team were already monitoring. They made sure that there was no sudden weight loss or weight loss below some safety level. So those are very different from regular people who are. Who may be even normal weight or even with within the healthy range. If they do, then they can potentially. So that's why what we think is eight to 10 hours maybe the ideal spot to begin with. And once you are physically active and you are also spending a lot of energy in physical activity or sports, you can even go up to 12 hours. Because in mice we have done that experiment up to 12 hours. They do get a lot of benefits. Not all, but.

A

So this is 12 hours of.

B

12 hours of feeding, 12 hours of fasting. Yeah. In humans, again, nobody has done systematically 12 hours, but there was one study in Europe from Tinhai Collet lab and Tinhai and I, we collaborate. So they used our mycircadian clock app. This is a research app. We developed just to. This is mostly used in time restricted eating studies. And he had nearly, I think he started with 200 swiss participants. But then at the end, he selected and took very small number of groups, people who are very meticulous about recording all their food, and divided them into usual feeding, whatever they wanted to eat, whenever they wanted to eat. And they were given the advice of swiss nutrition, advice that's given to improve health and reduce blood glucose, almost like diabetes prevention program in the US. And then the other group was given advice to eat within 12 hours. 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. The bottom line is, at the end of three months and six months, what he reported is both groups lost same amount of body weight. And then there was nothing too much significant difference between groups, but both groups actually improved their health. So the bottom line is, the swiss nutritional advice that he was giving, which is the standard of care there, it achieved the same amount of weight loss as just giving people this advice that eat within 12 hours. So one way to look at it, look at the result is like this. And then he went to more extent and actually looked at every single meal these people consumed. So there are, I think, close to 60 or 70,000 meal records and pictures he went through and then classified them to say whether these are good quality food. So they call it the Nova classification. 12341 is the food that you can almost eat raw fruits, vegetables, yogurt and dairy products that you can almost without any preparation. And then second, nova two is kind of 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 for unhealthy, ultra processed foods, which we should not be eating. So the advice is to reduce nova four. And what he found was people who got all this advice to improve their nutrition quality, they actually improved their nutrition quality. They reduced their novab for food. And people who were in time restricting, they ate within 12 hours. They did not change their nutrition quality. But what is interesting is they both got the same modest weight loss. So that begs the question that in the maybe Tinhai will do this experiment again to combine nutrition advice with time restriction and maybe reduce the time to 10 hours, and that might help. So, 12 hours is something that I say anyone from five year old to 10, zero year old can do. And if you are trying to maintain weight. That might be a good way. And combine that with exercise, it'll be great.

A

And people can more easily avoid reds in that way. Women. And for non athletes or recreational exercise, it sounds like women, if they distribute their calories across 12 hours, are less likely to lose their menstrual cycle.

B

Yeah, so again, this is something that we have to look carefully. They have to be, because we do have the my circadian clock app that many people download and self monitor and they share the data for researchers.

A

We will provide a link to that. By the way. It's a great tool.

B

Yeah. But once in a while we do get this input from some women saying, oh, I started doing your timeless eating and I'm seeing all these problems and I asked them, okay, so what else are you doing? They typically improve their nutrition quality. So they're eating only salad and few and they're trying to increase the 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 reds like symptom. So that's why I twelve, 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 ten 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 Dicava's finding from NIH. He has systematically done this study with two different types of diet and in mice, and he finds the same thing, that even mice that are eating within 12 hours, they do live longer than mice that eat randomly, even healthy food.

A

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 pressed 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 end time restricted. So these all caloric matched between groups and then non low carbohydrate diets. So sort of more standard. I think it was somewhere in the neighborhood of 60% of calories from complex carbohydrates. And as I recall the, the greatest weight loss, remember, same calories across groups, folks, was achieved with low carbohydrate plus caloric restriction. And I wondered why all the popular news venues didn't cover that study. But that's why I'm bringing it up now. I thought, this is really interesting, and I'm somebody who's cycled low carbohydrate diet before. I find it hard to sleep after about three or four days of being on a low starch diet, just personally. So I like to eat some starches, especially if exercising intensely or working intensely. That's just a little editorial there. But look, I know many people who do just feel better on a low carbohydrate diet. But what do you think of those data? Because it speaks to the idea that, okay, it's not just the total number of calories, it's not just the quality of those calories, it's the timing of those calories. And maybe carbohydrate restriction, in conjunction with time restricted feeding might be the best path for people who are looking to lose weight.

B

No, I totally agree that when it comes to nutrition, quality, quantity and timing, all these three matter. Nearly 40% of people who maintain healthy body weight, because 60% are overweight and 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.

A

So you're really an optimist. You're looking at the 40% of the glass. That's, or should we say not full. That was a pun intended, but the. No, that's a very interesting way of looking at. Rather than saying, why are 60% of Americans obese? Saying, why are 40% not obese? That's a very interesting way to look at it.

B

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

A

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 people. I actually think the pandemic had a lot to do with this. I think that people started to take a. 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. You seem to have aged backwards. So you are a poster for your own ideas and hypotheses about time restricted feeding. But I noticed that during the pandemic, a number of people emerged from the pandemic in better shape, other people in much worse shape. It seemed like it was like a bimodal distribution there. 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? Can you predict when you'll feel good enough to exercise? Maybe we could talk about that, because you, of course, are well known for time restricted feeding and the science around that, but also other things as well, not the least of which is circadian biology generally. So I always think of the main timekeepers for our system being feeding light activity and social connection. Did I miss maybe. And temperature.

B

Yeah.

A

Yeah. So how do these combine with one another? And using timing that we begin and stop feeding is kind of an anchor point. Can we explore that a little bit?

B

Yeah, so, you know, we got into this beginning and end, and then we. You asked for the calorie. How much calorie will break? The first one thing that I want the listeners and viewers to bring back to this timing of when we are breaking the fast, because we equate health with weight, body weight. And that's when we are talking about nutrition, quality and quantity, because both of them have impact. So now let's think about mental health, because a lot of people do struggle with mental health. They have anxiety or depression, and also gut health, because there are a lot of people who also have acid reflux or heartburn. And we know that acid reflux or heartburn can be exacerbated by caffeine intake in empty stomach. Those who have acid reflux or heart bone, they're prone to that then. And having black coffee in the morning before any food can upset their stomach. So that's why in those cases, it's very clearly that caffeine, for them, becomes the trigger that something, the food is supposed to come and then the stomach is not seeing the food, so it's overreacting, producing excess acid. And that comes up to the esophagus, and that's what they're experiencing. If people have that kind of condition, then maybe they should consider when they drink their first coffee, is breaking their overall fast or kind of putting their health at risk for acid reflux. The other thing is people who have anxiety, panic attack. We know that caffeine can judge you.

A

Off, especially on an empty stomach, especially.

B

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.

A

So do you avoid caffeine in the morning?

B

Actually, here is the interesting history about caffeine, and this is something I did not know, and I was once invited to this history of nighttime activity. And maybe we can take a little bit of detour and talk about nighttime activity, because that fascinates me as a circadian biologist, because over the last 200,000 years 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 a couple of thousand or 5000 years when we came to control fire, or maybe you can even go back to 100,000 years. There is some debate. So then the question is, well, when we control fire, and we lighted up the fire, and we could light up whenever we wanted, we can add fuel and we can stop the fire when we don't want it. That's the key ability in humans that differentiates them from all the other species. No other species. We can always say, yes, there are signs of this intelligent decision making. For example, we know many crows can make decisions. Many, 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 an evening that was very different from what people did during the day. And what people used to do during 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, so that we can, we could barbecue. 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, maasai and all these ancestors, sorry, populations that have no access to electricity and are still living kind of that historical life. Fire is a communal event. And they sat around, they cooked food. And then what happened? They did not talk about work. They talked about culture. They talked, they sang, they danced, they strategized. That's how politics started, philosophy started, science started. All of these things that are very unique to human civilization started around fireside chat. So 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, our social media.

A

And now we chat with our thumbs.

B

So it's still. So we are hooked to that evening activity because that's when we are completely free from the pressure of the work and we want to express ourselves. That's our independent time. So that's why most people find it very difficult to do time restriction and stop eating at 06:00 because it's ingrained 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 conjobs and particularly cafe, where people can come and have a little bit of coffee and socialize, it also started as an evening activity. And this is in. Now we can go back to Istanbul because that's one place where coffee cafes started in mid 16th century. So we are talking about 1540 to 1570. And that's when, I'm sorry, I'm forgetting the name of historians who actually invited me. And okay, his name is Cemal Kefadar. I must be butchering the name, but I'll try.

A

We'll 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.

B

Actually, I'm even checking right now in my endnote library. It's not picking up.

A

That's right. We'll provide a link.

B

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 sufi branch of Islam because they are the ones who consumed coffee in the evening. And this is the branch of Islam where they actually sing and dance and all that happened in the evening. So singing, dancing by the Sufi, and then here in Istanbul, people started congregating and having talk about politics. But then around the same time, some, you know, in Turkey, there was a good sizeable number of 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. 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.

A

Yeah. A few years ago, right before the pandemic 2019, I traveled to Turkey. First of all, the food is amazing. The coffee is indeed very, very thick. And I have a pretty high caffeine tolerance from drinking so much coffee and yerba mate over the years, and still do. I really enjoy it. But, yeah, it's very intense. And so what you're saying is that coffee intake started as a way to extend into the night. The ability to extend into the night at all was because of the ability to harness fire. And then coffees stimulatory properties were leveraged toward morning, which is essentially like, the way I think about it, we did an episode on caffeine, and someone else, Michael Pollan, not, I described it this way, that you're sort of taking a loan out on your energy bank account with coffee. You're suppressing the adenosine system. Adenosine makes you sleepy, but that adenosine system will kick in later. So it's a credit card of sorts with an interest, and the interest being an energetic lag that you're going to experience in the afternoon.

B

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

A

So coffee actually led to the development of breakfast, not the other way around.

B

But, yeah, so it does.