Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

I’m Andrew Huberman,

and I’m a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. Sachin Panda.

Dr. 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-hour rhythms

in everything from gene expression

to the overall functioning of tissues,

our levels of mood and alertness,

our ability to sleep, appetite, and much, much more.

In addition, over the last decade,

Dr. Panda’s laboratory has made critical discoveries

in terms of how our patterns of eating over time

impact our biology and our health.

In particular, his laboratory pioneered discoveries

related to so-called intermittent fasting,

also sometimes referred to as time-restricted feeding.

Today, Dr. Panda and I discuss how our circadian behaviors,

everything from when we wake up to when we view light

to when we avoid viewing light

to when we eat and what we eat

and when we socialize and how we socialize

impacts our biology and our psychology

and how all of that has a strong impact on our health.

During today’s discussion,

you will learn how restricting your feeding

to specific periods within each 24-hour cycle

or perhaps even exploring longer patterns

of fasting and eating cycles

can impact everything from the health of your liver

to your gut, to your brain,

and how all of that impacts things like mood

and your ability to perform cognitive work.

Indeed, today’s discussion goes deep

into all aspects of intermittent fasting,

aka time-restricted feeding.

We talk about the basic science

as well as the recent clinical trials

that have explored time-restricted feeding

in a diverse range of people,

including men, women, children, people with diabetes,

people who are otherwise healthy, and much, much more.

I’m quite aware that intermittent fasting

is a topic of much debate these days.

We go deep into that debate

and by the end of today’s discussion,

you can be certain that you will have learned

all the latest and all the details,

all made very clear to you

thanks to the incredible expertise, discovery,

and clear communication of Dr. Panda.

As some of you may already know,

Dr. Panda has authored several important books

on the topic of intermittent fasting

and how it can benefit various aspects of health.

Those books include The Circadian Code

and a more recent book, The Circadian Diabetes Code,

both of which we’ve provided links to

in the show note captions.

In addition, if any of you are interested

in learning more about Dr. Panda’s work,

including seeing his publications

and reading those publications

or supporting his laboratory,

you can do that by going to his laboratory website,

which we have also linked in the show note captions.

Before we begin, I’d like to emphasize

that this podcast is separate from my teaching

and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

to the general public.

In keeping with that theme,

I’d like to thank the sponsors of today’s podcast.

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And now for my discussion with Dr. Sachin Panda.

Sachin, Dr. Panda, so good to see you again.

Yeah, good to see you.

We are colleagues still,

but we used to be right across the street

from one another in San Diego.

Yeah, I remember those days.

Yeah.

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 post-mortem 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 as time-restricted feeding,

so-called intermittent fasting?

Does it have to do with how regular one is

about the start and stop times?

How do you think about defining intermittent fasting,

time-restricted feeding,

and maybe just to simplify the conversation,

is one term more correct than the other

in terms of describing this incredible pattern of feeding?

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 a hundred 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 AIDS-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 caloric restriction

is impossible or we are not doing it.

In fact, a lot of us,

we do count calories in our subconscious mind.

And so every time we take out a soda bottle or something,

I’m looking at, okay, 160 kilocalories,

30 kilocalories, zero kilocalories.

We are doing that.

So the point is we are doing subconsciously

some kind of calorie counting,

but reducing 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 the week?

So that led to this 5-2 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 period 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 was there.

Were those studies on humans?

Many of the studies started in mice,

but alternate day fasting, 5-2,

and Walter’s period 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 prediabetes

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 became, that umbrella term became intermittent fasting.

So if you look up the scientific literature,

most intermittent fasting involves

intentionally reducing calories

for at least one or two days in a week,

or a 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 eat the same number of calories

as the ad libitum fed mice,

but still they see health benefit.

So that’s why we call it time-restricted feeding.

But since it involves living without food for several hours,

for some people, which is, it can be very difficult.

The initial experiments was done,

they were done for eight hours of feeding

and 16 hours of fasting.

That kind of became popular.

And so that’s why people use the same term

as intermittent fasting.

And now if you say intermittent fasting

in popular literature or popular media,

then people usually refer to time-restricted eating.

So now coming back to how do you define

time-restricted feeding?

So the way we have been trying to define 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-restricted feeding

with four hours, six hours,

and some people even try to eat everything

within two hours, one meal a day.

But the point is those are not feasible

to maintain for very long time for a lot of people.

One question about the six hour versus eight hour

versus 12 hour feeding window.

Is it important that the feeding window

begin and end at the same time, more or less?

Yeah, more or less.

And if so, how much flexibility is there?

So for instance, I’m somebody that

I am not terribly hungry in the morning.

I like to drink water, usually some caffeine

and electrolytes in the period before my first meal.

And my first meal always lands sometime

between 11 a.m. and 12 noon.

There are exceptions, occasionally I’ll have a breakfast,

a proper breakfast as it’s called.

I guess it would be improper

if you’re intermittent fasting for me.

But typically 11 a.m. or noon is when I first eat.

And my last bite of food is typically around,

I don’t know, 8.30, 9 p.m.

That’s what works for me.

Is that consistency affording me any benefit?

And let’s just leave aside total caloric number,

macronutrients, plant-based meat, 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?

Yeah, so the start of the feeding window,

that’s interesting because the concept of time-restricted

feeding, when I describe animal studies,

it’s feeding for humans, it’s eating.

So the concept actually came from

the science of circadian rhythm.

So that means our body has an internal timetable

that’s present in every cell, in every organ

that 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 the mice during daytime,

the liver clock, instead of following its own routine,

liver clock actually started following food.

So that means by changing our feeding time,

we can change, we can tune our liver clock.

And subsequently, the same experiment

has been repeated many times.

And again, we repeated that in 2009.

And we figured out, yes, actually outside this brain center

called suprachiasmatic nucleus or SCN,

which is considered the master circadian clock,

almost the rest of the brain even follows when we eat.

And that came out from Pierre Chambon’s lab in Europe,

where they systematically looked at even places

that are very close to the SCN.

For those who know, those medial hypothalamus

or paraventricular nucleus, all of this,

within a couple of four or five millimeters of the SCN,

but they were following food cue.

Amazing.

So then, now if we think about it,

so for example, when the daylight seven time changes,

just one hour change,

or one hour change in alignment between our internal time

and external time leads to kind of feeling groggy

and feeling not at our peak performance

for one or two days.

So the rule of thumb is when the time giver

changes by one hour,

then our internal clock takes at least a day to catch up.

So that means if you’re flying from LA to New York,

you’re moving through three time zones,

then on an average, it will take three days

to catch up with the New York time.

For some people, it can be even slower,

and for some people, it can be two days,

but the bottom line is, yes, there is a desynchrony.

So then, what does it mean for the body?

So one of the functions of the clock

is to anticipate when you’re going to wake up,

for example, so the blood pressure slightly goes up,

our heart rate goes up, our breathing goes up.

Similarly, for food,

almost every organ that is involved in feeding

or eating, digestion, all of them have clocks.

So even from saliva production,

that is the first phase of digestion

to secretion of all the digestive juice in the stomach,

and then absorption of nutrient and liver metabolism,

everything, the whole village expects

when you’re supposed to eat,

and they’re getting ready for you to eat the first meal

after fasting for a long time,

so that’s why it’s breaking the fast or breakfast.

And when that time changes,

when you change it by two or three hours

from one day to another,

then sometimes they’re like, oh, food didn’t come,

or 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 that one day,

you have been eating every day at 8 a.m.,

I eat at 8 a.m.

Is that when you start your feeding window?

When does your feeding window shut?

6 p.m., so I eat for around 10 hours.

Okay.

And then one day, if I switch to 10 a.m.,

then what happens is a clock is thinking,

well, the food didn’t arrive at 8, but it arrived at 10.

Maybe tomorrow the food will arrive

somewhere between 8 and 10,

so we’ll be ready around 9.

I see.

And next day, if I come back and eat at 8 o’clock,

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.

Is there evidence that those anticipatory systems,

as they relate to digestion,

help us better assimilate our food?

I would imagine so.

I mean, if you have the gastric juices

that are gonna help digest the proteins, fats,

and carbohydrates already deployed

at the time when you eat,

I could imagine that food will be better utilized

than if you don’t.

So in other words, what is the advantage

of having these anticipatory signals

in terms of potential health benefits?

The anticipatory signal is really important

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 one hour early,

what happens, people who have underlying heart condition,

when they’re 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,

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 sharp rise in heart attacks.

And car accidents.

And car accidents too,

because your brain is not coordinated,

so you cannot make those fine decisions.

So that’s a great example of anticipatory activity.

But coming back to digestion,

one thing is,

and this is something

that many people might have experienced.

There are many rhythms in our digestive system,

and one of the rhythms is our intestine

has this peristaltic function,

so it kind of contracts and expands,

and that moves food.

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.

Yeah, I’ve experienced that

where if I’ve worked late

or I couldn’t eat dinner or something,

and then I get home,

I always debate whether or not to try and sleep.

But if I’m too hungry, oftentimes it’s challenging.

And so for me,

sometimes consuming something

that at least seems easily digestible,

like yogurt or something in a liquid form

is better for me than if I eat a meal.

I’ve made the mistake of going to the refrigerator,

being super hungry and eating a bunch of food

at 10 or 11 p.m. and then falling asleep.

And indeed the sleep,

if I’m tired enough, can be quite deep.

But the next morning I feel just completely,

physically and cognitively weighed down.

So I think what you just described makes a lot of sense.

So if someone were to select a feeding window,

regardless of whether or not it falls

into classic intermittent fasting, time-restricted feeding,

sounds like eating your first bite of food

and eating your last bite of food

at more or less the same time each day has benefits.

I have this question.

You mentioned feeding versus eating.

And I think it’s actually not just

a grammatical semantic issue.

And here’s why.

We tend to think about

when you take your first bite of food

and then when you take your last bite of food.

But of course, foods digest at different rates,

more fat in there is gonna 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 gonna eat my first meal every day

at noon and I’m gonna eat my last bite of food at 8 p.m.

and at 9 a.m. for whatever reason,

I have coffee with one teaspoon of sugar in it,

I suppose in the strictest sense, I’ve broken my fast.

But maybe by, if I went for a hard run that morning,

maybe by 9.30 a.m. I’m back in a quote unquote fasted state.

So what is the fasted state really?

Because when I’m eating at 8 p.m.,

just to give another example,

I start fasting at 8.01 perhaps,

but I have my blood glucose is elevated,

so I’m not really fasted, I’m fed.

It’s just that I’m not eating the verb, right?

Okay, so again, I don’t wanna 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 mile 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,

but because they all relate to the same theme.

Yeah, no, these are very interesting question.

And then unfortunately, as you might have seen in life,

the most obvious questions are often unanswered

because it’s so hard to do these damn experiments.

Because if you really want to address this in humans,

you have to bring humans, put them in isolation.

Just like you said, I can now imagine planning

five or six different experiments.

Each experiment should involve eight or 10 volunteers,

each gender, sex, and then do it.

So it’s difficult.

So now let’s go back to see how do we,

let’s dissect it in terms of say indirect calorimetry.

So for example, indirect calorimetry

is based on this principle that whatever oxygen

we breathe in and carbon dioxide we breathe out,

if we can measure these two, then we can figure out

whether our body in total, we are not saying

whether it’s the liver, gut, or fat, or muscle,

in total whether it’s consuming glucose

or fat as energy source.

The idea is when we are without food for several hours,

then ideally our body will tap 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.

Their metabolism is different.

They store relatively less glycogen than humans do.

In terms of total metabolism.

So they, overnight, within 12 to 14 hours,

the RER, respiratory exchange ratio,

or this ratio will go from one,

when they’re consuming mostly glucose or carbohydrate

as energy source, it will slow down,

slowly go to 0.7, 0.75.

So after 12 to 14 hours,

they’re kind of mostly running on fat.

So now, as we give them food,

within 10 or 15 minutes,

they’re not actually consuming couple of grams of food.

They might have consumed say 100 or 200 milligram

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.

When you say fat burning process,

you mean body fat stores being burned, right?

Not dietary fat, correct?

Yeah, so it’s all body fat.

Means that’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 absorbed

and digested and hopefully it’s sitting in the liver

or adipose tissue somewhere,

but it’s the fat that’s body fat.

Yes, thank you, Paul.

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 hope I don’t, I’ll probably get pitchforks

sent through the mail toward me on that one.

But I think that’s true,

whereas people who consume carbohydrate

can still burn body fat,

even though the majority of the fuel they’re burning

is from carbohydrates.

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 milligram of food,

and mouse runs around in the case,

and then we’ll continue to measure

to see how long it takes for the mouse to come back.

So that’s one aspect.

So now let’s see,

let’s stay on this,

and then I’ll come back and talk about non-caloric food

and whether that is considered.

I’d like to take a quick break

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So there’s a famous experiment

that was published last year by Jyotaka Hasislav,

and it came out in Science.

And that relates to caloric restriction.

And we kind of started with this idea,

we started discussing that the rat experiments

were done with caloric restriction,

and researchers gave reduced calorie consumption

by 20% or 30% and gave that food.

The rats, and then subsequently mice,

and they all lived longer.

What is interesting is, 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 restaurant now,

and just eat a little bit of lunch

and then snack after three hours or snack after three hours.

They gobble up all that food.

Within two to three hours, maximum four hours,

food is gone.

So they’re sort of on the OMAD diet, the one meal a day.

Yeah, they’re almost like in one meal a day,

three to four hours, food is gone.

Or you can say they’re on four hours eating or feeding

and 20 hours fasting.

So then the question became,

well, the benefit of caloric restriction, as we know,

is it due to reduced calorie or time-restricted feeding?

Or there is a timing component to it,

that they’re eating all of that within three to four hours,

and then there is a long fasting.

And this is a difficult question to answer,

because now you have to ask these poor grad students

or technicians to come and split that food

into eight or 10 or 15 different small portions

and then give them to mice in every two 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 case

where he could actually tell,

he could program how much food is given to mice

at what time of the day or night, completely programmed.

So then he took this, for example,

suppose say the ad libitum fed mice

eats five grams of chow in a day.

And if you want to reduce calories by 20%,

then the CR mouse should get four grams of food.

And he divided this into nine or 10 meals

and then gave them in every 90 minutes.

So in this case, they are eating small meals

throughout day and night.

So there is no fasting.

So you can say that, well,

this mouse actually is not getting into fasting

because in every few hours is getting some food.

And then he measured how long the mouse is going to live.

And he used account,

means 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 live certain number of days.

And then this caloric restricted mice

that never got into super fasting,

but kind of eating, snacking throughout day and night,

that also lived 10% extra, 10% longer.

So that means caloric restriction

extended lifespan by 10%.

I’ve wondered about this because recently,

you know, there’s been,

there were a bunch of news headlines

about intermittent fasting.

And 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, right?

And then another one that may be someplace

even more extreme, you know,

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, right?

And so I think that if we can segment those out,

obviously in humans, it’s hard to know

if a given treatment or experiment is extending life

because you don’t really know

how long people would live anyway, right?

Whereas with mice, you have some sense

of when the mortality was likely to occur.

So what can we say about time-restricted feeding

and longevity in terms of biomarkers

or in terms of any other indication

that people who start and stop their feeding window

at a consistent time,

somewhere between eight and 12 hours per 24-hour cycle,

are tilting the scales towards living longer

as opposed to living shorter?

This example of this news article that you mentioned

is really interesting

because that relates to Joe Takahashi’s study

because I described that if you split calories

and eat throughout the day, throughout day and night,

then the mice live 10% extra.

But if you now give mouse the same calorie-restricted diet

and feed them during daytime,

whether within 12 hours or two hours,

then the mice live 10% extra.

Beyond that?

Yeah.

So 20% longer?

40%.

So, 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-hour cycle,

it’s caloric restriction, the mice will live 10% longer.

If you, however, restrict that to the active cycle,

so for humans, the daytime,

then they live 20% longer.

20% longer.

So it’s not just total caloric intake.

Yeah.

Meaning it’s not just important

to be sub-maintenance in calories for sake of longevity.

It also is important as to when in the 24-hour cycle

you eat those calories.

Do I have that right?

So now, that’s still, the story is not over

because these mice are fed during daytime

and they’re not supposed to eat.

That’s right.

So for us, it would be the equivalent

of being on the night shift and only eating at night,

but a sub-caloric, sub-maintenance calorie diet,

I guess is the right way to say it.

But when you fed mice during nighttime,

when they’re supposed to eat,

and they’re getting the same number of calories

within 12 hours or two hours,

then the mice live 35% longer than they control.

35% longer.

So scaled 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?

The US life expectancy?

Yeah, so it’s around 80.

It used to be 80,

now it’s reduced a little bit because of COVID,

but let’s take 80.

Okay, so people are then now living

somewhere between 25 and 35 years longer.

I’m putting some error bars on there.

Yeah, yeah, yeah, yeah.

Amazing.

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 A1C equivalent

or glucose control, cholesterol, all this stuff.

He could not find anything that predicted

the benefit of caloric restriction.

So that means in this experiment,

whatever we know so far,

the predictor of longevity,

none of them could predict

whether this CR only mouse,

which ate throughout day and night,

that mouse is going to live less

than the night fed mouse

that was going to live 25% extra.

Does that mean that there are biomarkers

related to longevity

that we just haven’t discovered yet?

Yeah, so that’s exactly.

So that means whatever we know so far

about biomarkers,

those he could not use to predict.

Maybe there was a lot of noise.

Maybe he wanted,

he had to use more number of mice to get that

because biomarkers are not going to predict

in every instance that there is some error.

What is also very interesting is

if you look at the body weight

and body composition of all these mice,

there is no difference in body weight

and body composition.

Across all these different groups?

Across all these groups.

So it doesn’t matter when they ate,

provided they were sub-maintenance calorie intake.

So fewer calories than is required

to maintain their weight.

Didn’t matter what pattern of eating,

they were the same weight.

So that in many ways seems to mimic

the human studies where they say,

look, it doesn’t really matter

whether or not you use caloric restriction

or you start your feeding window in the morning

or start your feeding window in the evening

or you portion control for sake of weight loss.

Because you’re 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 10 hour sitting window

and the CR plus time restricted group

had to eat the same number of calories within eight hours.

So it’s just a two hour difference.

It’s just a two hours difference.

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

basically in a 10 hour feeding window,

which goes back to my first question,

which is that most people are not eating

in the middle of the night.

Or if they’re on shift work and they are,

then they’re sleeping during the day anyway.

So they’re eating in a 10 to 12 hour feeding window anyway.

So you’re saying they either did caloric restriction,

portion control within the 10 hour window

or another group within the study,

eight 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.

But it’s not all that surprising, right?

I mean, if it’s just a two hour difference.

Yeah, exactly.

So we have done that experiment in mice

and we don’t see difference in not only weight loss,

many other markers.

And I was telling you about this Joe Takahashi’s paper

where I told you that he allowed his mice

to eat within two hours or 12 hours,

sub-caloric diet.

Two or 12.

Two or 12.

Yeah, that’s dramatic.

But still he did not see change in longevity

even within those two.

So that means when you do caloric restriction

and then at least for mouse

and you are within 12 hours window,

that is giving the mice the best benefit,

the optimum benefit.

And two, three or five or 12 for a mouse doesn’t matter,

at least for longevity.

Can we conclude for humans that

whether or not a feeding window is four hours,

six hours, eight hours or 12 doesn’t matter

provided the calories are similar or same?

Well, I won’t go to that extent

because we don’t know many of these,

particularly we don’t know how this sort of eating window

will affect both sexes because we always think

many of these mouse experiments,

even that I told you about,

those are done only in male mice.

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.

So in this case, there are many,

I mean, 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

four hours or six hours of time-restricted eating,

people will inadvertently reduce their caloric intake.

Yeah, 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.

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 REDS, Relative Energy Deficit in Sports.

Relative Energy Deficit in Sports, okay.

Yeah, because nearly 40% of athletes,

not the NFL guys, but, you know,

there are a lot of people who do track and field,

and nearly 40% of athletes actually experience this REDS

without knowing.

Can male and female athletes both experience REDS?

So it’s REDS, R-E-D-S.

R-E-D-S, energy.

Relative Energy Deficit in Sports.

Interesting, this is the first I’ve heard this acronym.

We have a new acronym, folks.

This is good to add to a list of other acronyms.

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.

Yeah, so that’s so common, 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.

And-

Even if they don’t want to get pregnant.

Yeah.

Yeah.

Yeah, we had an expert on female hormones come on it

and say the very same thing,

that regular cycling is a-

Is very important.

Of ovulatory menstrual cycle is important

to try and maintain.

And so that’s one,

but then what is really concerning is

it does affect bone health.

And in this state, people actually,

over a long period of time,

they lose bone mass,

and their bone also becomes more prone to injury,

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 their 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 REDS

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 a few athletes who just can’t cope it.

And there are many attempted suicide or suicide.

So this is a serious issue.

And that’s also another new topic in the lab

to come up with a mouse model of REDS

and then study it.

But this is one risk,

why we should not reduce our eating interval

to one meal or a very short time,

because it can have adverse side 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 four hours and six hours time restricted eating

has benefits on weight loss.

But those are on healthy individuals

and they were in the study.

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 may be even normal weight,

even within the healthy range.

If they do, then they can potentially.

So that’s why what we think is eight to 10 hours

may be the ideal spot to begin with.

And once you are physically active

and you are also spending a lot of energy

in physical activity or sports,

you can even go up to 12 hours

because in mice, we have done that experiment.

Up to 12 hours, they do get a lot of benefits, not all.

So this is 12 hours of-

12 hours of feeding, 12 hours of fasting.

In humans, again, nobody has done systematically 12 hours,

but there was one study in Europe

from Tin Hai Collette Lab.

And Tin Hai and I, we collaborate.

So they used our MyCardianClock 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 was 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 not too much significant difference

between groups,

but both groups actually improved their health.

So the bottom line is the Swiss nutritional advice

that he was giving, which is the standard of care there,

it achieved the same amount of weight loss

as just giving people this advice

that eat within 12 hours.

So one way to look at the result is like this.

And then he went to more extent

and actually looked at every single meal

these people consumed.

So there are close to,

I think close to 60 or 70,000 meal records

and pictures he went through

and then classified them to say

whether these are good quality food.

So they call it the NOVA classification,

one, two, three, four.

One is the food that you can almost eat raw,

fruits, vegetables, yogurt, 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 a 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 a few other things.

And usually the NOVA four are unhealthy,

ultra processed foods,

so 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 NOVA four 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 Tin Hai will do this experiment again

to combine nutrition advice with time restriction

and maybe reduce the time to 10 hours,

and that might help.

So 12 hours is something that I say

anyone from five year old to 100 year old can do.

And if you’re trying to maintain weight

that might be a good way

and combine that with exercise, it’ll be great.

And people can more easily avoid reds.

Yeah.

And for non-athletes or recreational exercisers,

it sounds like women,

if they distribute their calories across 12 hours

are less likely to lose their menstrual cycle.

Yeah.

So again, this is something that we have to look carefully.

They have to be,

because we do have the MyCircadianClock app

that many people download and self-monitor

and they share the data for researchers.

We will provide a link to that by the way.

It’s a great tool.

Yeah.

But once in a while we do get this input

from some women saying,

oh, I started doing your time restricting

and I am seeing all these problems.

And then I asked them,

okay, so what else are you doing?

They typically improve their nutrition quality.

So they’re eating only salad and pew.

And they’re trying to increase their fiber intake.

And it’s really hard to eat so much of uncooked food

because cooking helps to absorb more nutrient.

And then at the same time,

they’re running five miles every day.

And of course all of this combinedly

can lead to reds like symptom.

So that’s why.

12 I think is a good point

if you’re combining physical exercise

and better nutrition quality,

because in mice also we have seen

that if mice are eating healthy food

and they’re eating within 10 to 12 hours,

then they also live longer

than mice that are eating healthy food,

but distributing that calorie over a long period of time.

And this is Rafa DiCabo’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.

I recall a recent study.

I think it was either published in Cell Reports

or Cell Reports Medicine.

Forgive me for not remembering which,

but both of course, Cell Press journals,

excellent journals,

which explored time-restricted feeding

in the context of low carbohydrate

or non-low carbohydrate diet.

So it was low carbohydrate

versus low carbohydrate and time-restricted.

So these are all caloric matched between groups

and then non-low carbohydrate diet.

So it’s a more standard,

I think it was somewhere in the neighborhood

of 60% of calories from complex carbohydrates.

And as I recall, the greatest weight loss,

remember same calories across groups, folks,

was achieved with low carbohydrate plus caloric restriction.

And I wondered why all the popular news venues

didn’t cover that study,

but that’s why I’m bringing it up now.

I thought this is really interesting.

And I’m somebody who’s cycled 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 that,

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.

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.

So you’re really an optimist.

You’re looking at the 40% of the glass that’s,

or should we say not full?

Yeah, that was a pun intended.

No, that’s a very interesting way of looking at it.

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.

Yeah, I mean, subconsciously,

we’re always making that decision.

And so I’m sure that you are not going

and eating cheeseburger every day

because you want to improve.

Yeah, exactly, I wouldn’t feel good.

Yeah, I enjoy a cheeseburger now and again,

but no, certainly not at this stage

or any stage of my life.

I think that, I think people,

I actually think the pandemic had a lot to do with this.

I think that people started to take a look

at what they were doing to support

or not support their health generally.

I know people gained a lot of weight during the pandemic.

Other people got really into fitness.

I’ve seen some colleagues, so you’ve always maintained,

you’ve always been in good shape.

Actually, this is the first time I’ve seen you in a while

and you seem to have aged backwards.

So you are a 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?

Like, can you predict when you’ll feel good enough

to exercise?

Maybe we could talk about that

because you, of course, are well-known

for time-restricted feeding and the science around that,

but also other things as well,

not the least of which is circadian biology generally.

So I always think of the main timekeepers for our system

being feeding, light, activity, and social connection.

Did I miss?

And temperature.

Yeah.

So how do these combine with one another?

Using timing that we begin and stop feeding

is kind of an anchor point.

Can we explore that a little bit?

Yeah.

So we got into this beginning and end,

and then you asked for the calorie,

how much calorie will break the fast.

One thing that I want the listeners and viewers

to bring back to this timing of when we are breaking the fast

because we equate health with weight, body weight.

And that’s when we are talking about nutrition quality

and quantity because both of them have 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 heartburn,

they’re prone to that.

Then having black coffee in the morning

before any food can upset their stomach.

So that’s why in those cases,

it’s very 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.

So if people have that kind of condition,

then maybe they should consider

when they drink their first coffee

is breaking their overall fast

or kind of putting their health at risk for acid reflux.

The other thing is people who have anxiety, panic attack,

we know that caffeine can jazz you up.

Especially on an empty stomach.

Especially on an empty stomach.

So for them, again, caffeine can be a trigger.

So that’s why I want to kind of differentiate

that there is this mental health

and other aspects of health.

And these are two clear examples

where anxiety, panic attack related to brain health,

or acid reflux related to our gut health.

In those cases, when we consume that caffeine

in the morning can affect.

So.

Do you avoid caffeine in the morning?

No, actually, here is the interesting history about caffeine

and this is something I did not know.

And I was once invited to this history

of 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,

couple of thousand or 5,000 years

when we came to control fire,

or maybe you can even go back to 100,000 years,

there is some debate.

So then the question is, well,

when you 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 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 the day,

they walked a lot,

means gathering food was almost everything that we did.

And so in the evening after we brought food,

mostly tubers or maybe lentils to cook

or once in a while animals so that we could barbecue,

all of those 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, 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 war.

They talked about culture.

They sang, they danced.

They strategize.

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.

So now we chat with our phones, right?

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 timeless eating and stop eating at six o’clock

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?

And if you look at coffee consumption,

particularly cafe where people can come

and have a little bit of coffee and socialize,

it also started as a evening activity.

And this is in, now we can go back to Istanbul

because that’s one place where coffee cafes

started in mid 16th century.

So 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 Keferdar.

And I must be butchering the name, but I’ll try.

We will provide the spelling.

And the wonderful thing about social media

is somebody will tell us on YouTube,

the proper pronunciation.

So this is a great opportunity.

If you know the proper pronunciation,

please put it in the comments on YouTube.

Actually, I’m even checking right now

in my EndNote library, it’s not picking up that.

That’s right, we’ll provide a link.

So what happened was, so coffee was introduced

and people came and drank coffee and talked about politics.

At night.

At night, at evening.

And it actually started with Sufi branch of Islam

because they are the ones who consumed coffee

in the evening.

And this is the branch of Islam

where they actually sing and dance

and all that happened in the evening.

So singing, dancing by the Sufis.

And then here in Istanbul, people started congregating

and having talk about politics.

But then around the same time,

some, you know, in Turkey,

there was a good sizable 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 when they woke up.

So that’s how it started as a morning drink,

to stay awake and kind of get on with the day.

But what happened was,

I don’t know whether you have ever tried Turkish coffee,

it’s very thick.

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 in 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 coffee’s stimulatory properties

were leveraged toward morning,

which is essentially like, the way I think about it,

we did an episode on caffeine and someone else,

Michael Pollan, not I, described it this way,

that you’re sort of taking a loan out

on your energy bank account with coffee.

You’re suppressing the adenosine system,

adenosine makes you sleepy,

but that adenosine system will kick in later.

It’s a credit card of sorts, with an interest, right?

And the interest being an energetic lag

that you’re going to experience in the afternoon.

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.

Ah, so coffee actually led to the development of breakfast,

not the other way around.

Yeah, so-

That’s very heartening, again, no pun intended,

for the caffeine lovers among us,

which I count myself one of those.

So essentially, the food before coffee became breakfast.

So you kind of give something to your stomach,

so it’s busy digesting that.

And then when the coffee comes in,

it’s not reacting to coffee and creating acid reflux.

So it wasn’t, it’s fascinating.

So it wasn’t that breakfast is necessary on its own,

it was essentially a buffer against the gastric distress

caused by caffeine intake.

At least in that culture, in that context.

We cannot say that whether the same thing happened

in all over the world where coffee is not consumed,

but still people eat something in the morning.

You said you start your first meal of the day

at around eight, what time do you wake up?

I wake up around six, 5.30 to six.

What time do you have your first caffeine?

So that’s why I brought up this story

because I have coffee after my breakfast.

Fantastic.

I’m a big proponent of delaying caffeine intake

for a few hours after waking,

for other reasons that my listeners

have heard me talk about endlessly,

so I won’t bother with that now.

But I think allowing,

just suffice to say that allowing

some of the natural waking up signals to occur

and using light to kind of clear away

and adenosine to further extend an activity

is better than using a stimulant,

but until a few hours later.

This is fascinating because I’ve never thought

about the link between extension into the night,

socialization, or socializing rather,

feeding and caffeine.

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Now, actually, I’m kind of speaking

what many other researchers have found,

and this particularly, this fireside chat,

I’m forgetting again the name of the scientist.

I think she’s from University of Washington, Seattle.

She went to Africa and kind of recorded

what people are talking.

Of course, she could not understand what they were talking.

Twitter and whether or not Tesla’s stock is going up,

of course.

No, no, no, just kidding, folks.

And then came back and tried to translate

and then figured out that what they were talking

during daytime and in the evening were very different.

What are they talking about at night?

Exactly, so this is like,

they’re talking about matchmaking

and talking about politics and strategizing

to gather food or even singing and dancing.

So this is, if we think about it,

how we manage sunset to our bedtime,

what we do between sunset and bedtime

affects most of our health.

I’m gonna think about that for a moment.

I totally agree.

And by the way, I’m a huge believer

and I’m living in great hope for the idea

that right now, I do think that scientists understand

a lot more about the different stages of sleep,

slow-wave sleep, REM sleep, et cetera,

than we do active waking states.

Like we talk about being focused or being alert,

but those aren’t scientific terms, as we know.

But I do believe, and I’ve noticed a distinct difference

between the first eight hours of the day

in terms of cognition.

And we know that the catecholamines

are at much higher levels plus cortisol.

So dopamine, cortisol, epinephrine,

all of that is really at much higher levels

than in the later evening.

And so this evening time,

it’s certainly in the context of mental health.

We know that morning and evening,

we are basically different creatures.

Yeah, completely.

Yeah, so that’s why I think in the evening,

if you think about it, again,

this is, again, another set of research

from my good friend Horacio who-

The Iglesias.

Yeah.

Oh yeah.

I’m a big fan of Horacio’s.

He’s a fellow Argentine.

So occasionally we riff about things related to that,

but he’s a wonderful biologist.

Are you guys collaborating?

Yeah, he’s kind of, I say he’s very humble

and keeps a low profile,

but he does amazing, amazing research.

Totally agree.

And he does research that we want to know,

but nobody is ready to do it

because field research is very difficult

to go to the wilderness or go to the places

where there is no electricity

and then record when these people are eating,

sleeping, or in this case, activity,

exposure to light.

That’s what Horacio has done.

And he puts this active watch,

which is kind of a modern activity tracker,

but it’s a little bit more refined

because it also collects light information.

What he found was most of these Argentinian tovas

who have no access to electricity,

they consistently go to bed

somewhere between three to three and a half hours

after sunset.

So this is very important

because we always think that our ancestors,

when they didn’t have electricity,

as soon as the sun went down,

they just went to sleep.

No, the fire extended their evening.

So they were staying awake for three to four hours,

kind of decompressing themselves, that we say,

and then doing all these activities,

cooking, sharing meals,

and then they would go to sleep.

And if you look at the sleep onset variability,

it was very small.

Like they’re going to bed

almost within 15 to 30 minutes standard deviation.

So no night owls versus morning people.

Exactly, so we’ll get to that.

None of this, I get attacked for many reasons.

It just goes with the business I’m in

of being public facing these days.

But every time I talk about viewing sunrise

or low angle sunlight,

getting some sunlight early in the day,

someone says, well, I’m a night owl.

And it’s almost like a protest

of trying to protect identity.

It’s become this ideological identity related thing.

I’m a night owl.

I’m a morning person and I’m not.

But you’re telling me that in these cultures

where there isn’t electricity, but there is fire,

people are going to sleep within all of them,

within about 15 minutes of one another.

So there is no such thing as a night owl

or a morning person in the context.

Yeah, so Horacio actually asked him pointedly

because, and then he said, no, he has not seen.

Means he has tracked hundreds of people.

And if we ask, there are many, many sleep researchers

or at least the public facing sleep physicians or experts,

they will say, yeah, we can say one third of people

are night owl, one third are morning,

and then one third are in between.

But-

Yeah, they call them like bears, wolves,

and I’m not being disparaging of that idea.

I think people really do feel as if they orient

towards one pattern or another.

When I was an undergrad student,

I never went to bed before midnight.

And actually, midnight was my going to bed time.

Exactly like 11.45, I’ll try to get ready to hit bed.

And then by 12, I’m in bed.

And I used to get up at 6, 6.15.

That’s still, that’s a pretty short sleep.

With an alarm, of course.

But then daytime, I used to take 45 minutes to one hour nap.

And that was regular.

Like, even if, whenever I got time.

Of course, in college, you know,

you don’t have the whole day.

Unlike in high school, you don’t have opportunity to nap.

But in college, you can.

I might’ve been one of those kids

with his hoodie on napping on the desk,

but they come around and they wake you up.

Yeah, but in this case, just come back to the dorm

and after lunch, usually I used to take nap.

So then in grad school,

I remember I rarely went to bed before 2 a.m.

And I could have clearly said that I’m a night owl.

And actually, I was a night owl.

I was very comfortable staying up so late.

I was very productive, doing experiments,

writing all these manuscripts mostly.

But then afterwards, when I look back in post-doc,

when I had, when we had our daughter,

then things started changing

because you have to put the baby to sleep.

And then after the baby sleeps,

it’s almost when you have a baby,

your life revolves around the baby.

So then we had to dim down the light.

There is no caffeine and alcohol drinking

or any other things after the baby sleeps

because we cannot do too much noise.

So then I realized that, no, I’m actually not a night owl.

And I became kind of more normal

because I could go to sleep between 10 and 11.

And that’s how I thought,

well, maybe this was very unique to me.

But what is interesting is I have another colleague,

good friend, Ken Wright Jr.

At Colorado.

At Colorado.

And he also had grad students and post-docs like me

who strongly believed that they were night owls,

just like everybody else.

And Ken took the whole lab for camping.

And when they were camping, of course, there is less light

and a lot of physical activity, hiking during the day.

And they all went to bed between 9 and 10.30 p.m.

I love that study.

What Sachin just described was a study.

I think there were two studies.

There were two, yeah.

And what’s interesting, as I recall,

was that after going camping for a weekend

where people wake more or less with the sunrise

and go to sleep a few hours after sunset,

their melatonin rhythms and cortisol rhythms

and sleep-wake rhythms persisted on that schedule

for several weeks, despite returning to environments

where there was a lot of artificial lighting,

which I find amazing that just a weekend

of consistent rising and going to bed

with the sunrise and sunset, more or less,

allowed a reset that was very long-lasting.

Yeah.

So actually, even in Horacio’s study,

he found that almost all the tovas,

they wake up around sunrise time.

And it’s amazing when I look at the standard deviation,

it’s like so tight.

So take that, night owls, so-called night owls.

I also, in graduate school, I would work until 2 a.m.

I loved it.

I would blast music in the lab.

Everyone was at home, pretty much.

Not everyone, but there were the night crew.

And then I’d get in sometime around,

get up sometime around 9.30, 10,

and then get in around 11, and it was no problem

because I was going to stay so very late.

And then over time, I noticed I’d become more locked

to a standard schedule.

So I think what we’re saying is that the clock can,

our internal clocks can shift,

but this idea that we are genetically biased

towards one schedule or another may need revisiting.

That’s the conclusion I’m taking from this.

Yeah, there are a couple of aspects.

One is, you know, some people are genetically

so pre-programmed because the other flip side

is what is called technically

familial advanced sleep phase syndrome.

So these people, you can give them caffeine or whatever,

but they will fall asleep, say, at eight o’clock.

They cannot stay awake till nine or 10.

And since it’s a very strong phenotype

in sleep and circadian rhythm field,

they are very well studied.

So in fact, Louis Ptacek and Nguyen Phu,

they were the first one to track one family like this,

and then they figured out there was a mutation

in one of the clock genes, period two, that clock gene,

and that mutation allowed the clock to run in a way

that these people went to bed very early.

I guess historically, given these fireside chats,

those people were probably not contributing much

to the political discussion.

Whatever there was decided after they went to sleep

is what they woke up into.

That reminds me, because as you were describing

the difference between nighttime discussions

versus morning discussions,

is there any theme to what is discussed in the morning

versus in the nighttime,

or are people just sipping their,

eating and sipping their caffeine and just waking up?

But are there any ideas

about what morning discussions really consist of?

Morning discussions or daytime discussions

are mostly about work,

and like hunting, gathering, or farming, all that stuff.

And even these days, that’s what we do.

I go to work and it’s mostly one meeting after another,

and we’re talking about how,

means if you’re in different committees

and you’re solving problems,

or your students come with questions,

you have your TA or the office hours,

all these things, work-related.

We’re not talking, I mean, serious philosophy,

unless you are in a philosophy department

and you are talking about political science.

And also, we are not singing and dancing.

So that’s why the evening activity,

even these days, are very different.

And typically, the evening activities

are where we express ourselves.

We express who we are.

We feel like we are free.

And you and I, we have this academic intellectual freedom.

We can talk about our work, just like we are talking now.

There are a lot of people who work for,

even in tech industry, they may be working for Google

and all these big tech companies.

They cannot talk about their work to anybody else.

It’s all secret.

It’s all secret.

So just imagine, they’re staying,

so they’re spending more than half of their wake-up time

at work, thinking and doing work,

but they cannot talk about that work,

even sometimes to their own family members.

So then what happens for them,

a lot of people also do the same thing,

like the person who is going and baking

in a restaurant or cooking,

or the person who is taking trucks and driving.

Or nurses and doctors can’t talk about their patients.

There’s confidentiality.

Yeah.

And some people just don’t want to talk about it.

It’s so stressful.

They don’t want to bring that stress home.

So that’s why I always say that from sunset

until we go to bed, during that time,

we try to find time for ourselves.

People say, this is me time.

The me time is essentially,

we want to truly express who we are,

or we want to entertain ourselves.

Because on the fireside chat,

it’s not that everybody was a performer.

There are also some audience.

So we always switch our roles.

Sometimes we are performing,

and sometimes we are observing.

So that’s what happens with me time.

I love this.

So maybe social media time should be restricted

to just maybe a small portion of that evening time.

Because I would hope that people

would also interact socially in the real sense.

Or maybe in a constructive way,

or maybe you use that to connect with your family members,

whom you love,

or you can have some productive discussion or something.

So it’s kind of interesting.

I think it’s extremely interesting,

because I think, again,

this conversation about time-restricted feeding

is really a conversation about-

Cicadian rhythms.

And sleep-wake activity and human evolution, right?

So that’s why, let’s go back to this night owl.

Because we kind of made a comment

that maybe it’s not genetic,

but this is where I’m still wrapping my head around.

Because these days, there’s some GWAS studies

where they’re trying to look at night owls

to see whether there are some genetic linkings.

And sometimes we always think,

yeah, if you take half a million people,

of course you’ll find some loci.

But going back to this idea

that are some people more sensitive to light,

so that it’s likely that the same level of light,

even in the same household,

may make some people stay awake late into the night,

whereas other people are more resistant to light,

so that they can go to bed early.

And since light has become so prevalent these days,

and this TOBA story that we are talking about,

or people going on camping,

that is, we have removed that light.

So there is some evidence that people’s light sensitivity,

particularly the IPRGC,

or this intrinsically photosensitive retinal ganglion cell,

or the simple speak is the blue light sensors in our eyes,

there seems to be even one log unit change in sensitivity

as measured by pupil constriction.

So for some people,

a small amount of artificial light at night

could really shift their circadian clock,

wake them up, essentially.

And then for some, it may not.

Yeah, I’m very sensitive to light at night,

exquisitely sensitive to it.

Oh, so then you are like a teenager.

Yes, in many ways, I’ve been told this, thank you.

Yeah, I think.

I have actually switched to using a red night light,

but I should be clear,

not a fancy high cost red light

for sake of any kind of infrared simulation,

but a red party light type light.

And I find that was based on reading one study

that we covered in an episode on jet lag and shift work,

which was that it seems to reduce

the cortisol releasing properties of light at night

to use red shifted light.

So I just use a red light bulb.

I actually travel with one.

If I go to an Airbnb or a hotel and I switch to red light,

and I find that I fall asleep and stay asleep

throughout the night much more consistently,

especially when I’m in new environments,

which always makes it disruptive to sleep.

It’s made an enormous difference

in the depth and duration of my sleep.

And because oftentimes hotel lights,

you know, in the bathroom, you’ll turn them on,

you’re just getting beam.

And you’re right, some people don’t seem

to be bothered by that.

I really struggle with that.

Yeah, and in fact, in teenagers, right after puberty,

there seems to be, I think that’s when the teenagers

become more sensitive to light.

And it’s very, it’s well known

that the teenage boys and girls,

they tend to stay awake late into the night

and they can stay up to 12 past midnight.

Although they can stay up that late,

that doesn’t mean that their sleep schedule is reduced.

Their body still needs the same amount of sleep

as other teenagers.

So that’s why they are more likely not to wake up

at 6.30 or 7.00 when we expect them to wake up

and go to school.

I have a question and I ask every circadian

related biologists that I can come into contact with this,

and no one has been able to give me an answer

one way or the other.

But I grew up hearing that every hour of sleep

before midnight was of more value or potency

than the hours after midnight.

And indeed I find that if I go to sleep at 9.30 or 10.00 p.m.

I can wake up at three or 4.00 a.m.

feeling pretty fantastic and ready to lean into the day.

But if I get the equivalent number of hours of sleep

starting at midnight, I feel like complete garbage

when I wake up after five, six hours.

So is there any truth to the idea that going to sleep

within three hours of sunset is somehow better

for our circadian timing mechanisms?

Well, there are a few things.

One, you said that you are very sensitive to light.

So I assume that you also avoid bright light in the evening.

As best I can, yeah.

As best as you could, can.

And then what is happening is with absence

of that bright light, your melatonin levels begin to rise.

So you are prepared for sleep.

Of course, this is something that we cannot measure

because measuring melatonin in every one hour

or 30 minutes is very difficult

and there is no consumer-facing product yet.

So it’s likely that your body is preparing very well

under this dim light to fall asleep.

And when you are trying to stay awake

and go sleep at midnight, then maybe from midnight

for the first three or four hours, you are sleeping well.

But then after that, your melatonin level

might be beginning to fall.

And it’s not only melatonin, your core body temperature

and then your heart rate and everything is changing

to make you awake.

But the sleep debt that you have accumulated

is pushing you to be in bed.

So there is this tension between the circadian aspect

and your sleep debt.

And unfortunately, you cannot have good night

of restorative sleep for the second half of the sleep

because of the tension.

That makes good sense.

Yeah, so that’s why you are not the only one.

There are many people who experience that.

And in fact, a lot of people think that,

well, this may be the way I sleep.

Maybe I am not designed to sleep restoratively

until I sleep one day, just like the camping trip.

And then they realize what it feels like

to be haphazardly asleep.

What you are missing, yeah.

Absolutely.

I want to make sure that we talk about

the other aspect of fire, which is you had a paper

that came out recently, very interesting paper,

studying firefighters and time-restricted feeding

in firefighters.

Would you share with us the general contour

and maybe even some of the specifics of that study?

Because I think it’s very interesting

for sake of shift workers, but for everybody really

to understand these results.

Yeah, so let’s go back to shift workers

because this also relates to all of us

because I always say that each of us is a shift worker

or has lived the life of a shift worker.

And we have experienced how terrible, difficult it is.

And now let’s start with what is the definition

of a shift worker or shift work-like lifestyle?

There is no universal definition, unfortunately,

but there are many European countries,

and particularly if you go

to international labor organization,

then you’ll find some references.

Different European countries

have slightly different definition,

which essentially points to,

if you stay awake for two or more hours

during your habitual sleep time,

and when they say habitual sleep time,

they assume that we are, just like you said,

we are kind of programmed to sleep

somewhere between, say, 10 p.m.

and then stay in bed and kind of wake up after 5 a.m.

So the idea is if you’re staying awake

for two or more hours between 10 p.m. and 5 a.m.,

and you are engaged in some activity,

whether it’s physical activity or intellectual activity,

you are not lying in bed and wondering,

worrying about something, but actually working.

So that’s defined as shift work,

and you don’t have to do it every single day.

Even if you do it once a week for 50 weeks,

then that itself is enough to disrupt your physiology

and metabolism, behavior, brain function,

like a shift worker.

The reason is, as we discussed,

when you change our external timing cue,

so in this case, when you travel jet lag

or traveling across three days,

three hours of jet lag will take three days to reset.

Similarly, if you’re staying awake for two hours extra,

or if you’re waking up two hours

before your habitual wake-up time,

then we just don’t wake up

and then be engaged in some activity in the dark.

Most of us, unless you are wearing infrared goggles,

we turn on light, and light resets our clock.

So in that way, every time we stay up

for two or more hours, even for one night,

then for the next two nights,

our clock is kind of trying to catch up.

So in that way, for three days,

the day of the disruption,

and then two days following the disruption,

our clock is trying to catch up with the outside time.

So our body is not on time with our clock.

So that means almost for half of the week

or half of the year, our clock is trying to catch up.

So that’s the definition of shift work.

So now let’s come back

to Department of Labor Statistics, U.S. government.

They have not been tracking

what percentage of people are doing shift work accurately,

because there are many difficulties in tracking too.

But it’s generally accepted

that one in five working adults

is a card-carrying shift worker.

Card-carrying shift workers means they are nurses,

doctors, firefighters,

and bakers, truck drivers,

and many in the service industry.

So that’s one in five.

So 20% of working adults.

Then if we think about all the college students,

just like I was doing, and you must have done,

there are also-

Deadlines, granted deadlines.

Granted deadlines.

Then we are also experiencing

the lifestyle of a shift worker,

because we’re delaying sleep.

Even if you’re delaying sleep by two hours

for most of the college students for five days,

and then the weekend you’re trying to catch up,

that’s kind of a circadian disruption going on.

Then you take 1.5 or 1.6 million new moms

in the U.S. every year.

So when the child is born,

then that mother is a shift worker.

Actually, that mother is worse than a shift worker

because you don’t know what time of the night

the baby will wake up and how many times,

and there is no weekend in motherhood.

So they’re also living the life of a shift worker.

We don’t count many food delivery and Uber driver,

Lyft drivers as shift workers,

but many of them we know that they live.

So in that way, we think the actual number of people

who are experiencing the life of a shift worker

is somewhere around 50% of the adult’s population

at any given time.

So that’s why it’s also another point

that you might have heard from people.

They will say, oh, I cannot do time-restricted eating

because my schedule is messed up,

or I work in a different way,

and that comes into play.

So that’s why we thought,

okay, so we should try something on shift worker.

Another point is although one in five people

are shift workers,

they carry disproportionately heavier burden of disease

because almost all age-related disease

that we can think of, whether it’s high blood pressure,

usually high blood pressure starts in 40s or 50s,

high cholesterol, gastrointestinal problem, indigestion,

chronic inflammation of the colon,

and then even colon cancer in many cases.

And then, of course, diabetes,

all of these are disproportionately more prevalent

among shift workers.

But then when you think about clinical trials,

whether it’s a drug or a lifestyle,

often one of the top 10 exclusion factor criteria

is shift work.

So people who are doing shift work,

we exclude them from many of these trials.

One thing is most physicians and most scientists,

even people who do shift work,

they know that their body and mind is so messed up

that oftentimes even medications may not help them.

And so that’s why we don’t try a new medication.

Why to take the risk when we know it may not help them?

And then when it comes to lifestyle intervention,

whether it’s sleep extension, for example,

we cannot do because they are supposed to stay awake

and do their job.

We cannot ask them to stay asleep at night.

And then physical activity and exercise,

some people can do,

but some people are so tired after all night

that they don’t have the energy to do physical activity.

And then nutrition, again, most nutrition studies

involve the participants to come to the clinic

and get one-on-one or attend group sessions,

and they cannot come.

And they cannot even sometimes come to the clinic visit

when people have to draw blood.

And in fact, there is another caveat that just if,

suppose I’m healthy,

I have perfectly normal blood pressure,

blood glucose, cholesterol, everything is normal.

And I live the life of a shift worker just for five nights.

That means I’m sleeping less, maybe four or five hours.

And even if I don’t eat at nighttime,

of course, many shift workers also feel hungry

and just to keep their work, they eat.

Just after five days, my blood glucose level

will read almost like I’m pre-diabetic.

Wow.

I actually saw a study in published in Proceedings

of the National Academy

that showed that even a hundred lux dim light

present in the room while people are sleeping

with eyes closed can lead to disruptions

in morning blood glucose levels

in directions that are not good one night.

So the faint clock in the corner

or even a nightlight that’s too bright

could be problematic.

By the way, folks, these effects are reversible.

So whenever I say these things,

we get a lot of comments about,

oh my goodness, what have I been doing for years?

Kids with nightlights, this is an issue.

But what I’m hearing is that one in five people

are truly shift workers in the classic sense.

Their jobs require they work at night

or into the night and sleep into the day.

But far more people are shift workers

by virtue of the fact that they’re tweeting

or working or watching movies at night,

even though it’s not work

in that they’re not being paid for that time.

They are essentially operating like shift workers.

If we add those two groups together,

would we say it’s what, a third of Americans?

I would say half of Americans.

Half of Americans.

Yeah, if you take teenagers,

because high school students and college students,

because again, going back to Horacio’s study,

because Horacio also collected activity data

from high school students and college students,

and we have replicated that with high school students

and college students in San Diego.

So that’s Seattle and San Diego.

And this study, now there are many sleep researchers

that have been collecting this data.

And what we find is typically the high school students,

they are going to bed say around midnight

and college students, at least the UCSD students,

we found maybe one out of 100

who went to bed before midnight.

That reminds me that Horacio Iglesias

just published this really nice paper

showing that counter to what we believe,

now this is the University of Washington in Seattle,

I should mention, where it’s very dark in the winter.

Young people, these are people in their 20s,

are staying up later in the winter months

compared to the summer months.

Which is totally counterintuitive.

You think, okay, everyone stays up late in the summer

and goes to bed early in the winter,

but because of artificial lighting, it’s the exact opposite.

Yeah, so another, I don’t know whether Horacio monitored it,

but my other suspicion, I’m not saying whether it’s true,

in winter, we are more likely to consume more coffee,

hot chocolate in the evening,

and that might also be delaying sleep onset.

That makes sense.

So in that way, again, here is another thing

which can be related to policy

or practice at Educational Institute.

So what happened during COVID

was everybody went to remote learning.

The assignments became digital

and assignment submission became digital.

And there are many systems, online systems,

that came into play.

And by default, the assignment submission deadline

became midnight.

So then now what is happening is,

I don’t know about Stanford,

maybe when you are giving assignment,

what is the deadline?

Midnight, typically.

Midnight.

So then most of us, most students,

they will try to cram as much as possible,

try to solve as much as possible,

and submit at midnight.

And it’ll be really cool to go back

to your system administrator to see,

is there so many frequency plot of,

frequency distribution of what time

people are submitting their assignment.

Because we know, when we submit our grant.

Yeah, so, I mean, you hear about the obesity crisis,

the crisis of metabolic disorders,

not just in the US, but everywhere in the world.

I mean, it’s really striking.

I remember going to a Keystone meeting,

scientific meeting in the early 2000s.

And there was a map of the United States

and it showed where the obesity rates

were over 30% in adults.

And the entire country basically was lighting up like crazy.

Now it would be the entire country.

But there were these kind of zones in the middle

that were almost devoid of obesity.

Colorado, namely, Idaho at that time.

Those are now also fallen under the umbrella

of rampant obesity.

And everyone is speculating,

okay, is it seed oils?

Is it this, is it that?

Is it highly processed foods?

I’m guessing it’s all of those things,

including lack of activity.

But one has to wonder,

given everything we’re talking about

in terms of metabolic dysfunction,

late shifted eating, all these issues

with late shifted eating

and staying up late with artificial lighting,

whether or not that could be one of the major factors

in the so-called obesity crisis.

It’s likely, you know, we call it a freshman 15.

That’s right.

These kids are gaining 15 pounds

in their freshman year in college.

And this is where I think as educator or professors,

it’ll be interesting to go back and see what can we do?

Because another thing that’s also becoming

more and more common,

for example, I give a circadian rhythm class,

means I just give two lectures.

And I remember when I started 15, 17 years ago,

that lecture used to be around 1.30 p.m.

or 2.00 p.m. in the afternoon.

And it’s a two and a half hour lecture.

So it’s done by five.

And for the last, before the pandemic,

I realized that they changed the timing.

Now the lecture was starting at 7.00 p.m.

So I was finishing by 9.00, 9.30 p.m.

And these kids, they had to go and eat after 9.30.

Study, socialize.

Study, socialize.

Fireside chat.

Fireside chat.

And then to express themselves,

like to feel free from assignments.

When are they going to do that?

After they submit the assignment,

then they’re going to do that.

So that’s why we had to go back and revisit this issue.

Say, okay, so for adults,

for most of us who are working a day job,

our deadline is 5.00 p.m. in most cases.

Means at least in university system,

the person who is submitting the grant

who is taking care of my IRB or IACUC,

they are all leaving at 5.00.

So for me, everything has to end by five.

I think for most people out there.

So this raises a kind of macroscopic question,

which is maybe it’s not so much

about restricting the feeding window,

but maybe it’s about feeding mostly and being active

mostly in the early part of the day.

I mean, I could imagine a time three, four years from now

when waking up early and going to bed

within three hours of sunset is the protocol

which harnesses all other protocols, right?

And you’re going to exercise,

you’re going to do it in that time.

You’re going to eat, you’re going to do it in that time.

You’re going to socialize, you’re going to do it in that time.

And in doing so, you’re also avoiding a lot of the issues

related to disrupted sleep.

So that’s why all these things, as you said,

time-restricted feeding is just one aspect

of the circadian health and these are all interconnected.

And going back to the comment

about within three hours of sunset, yes, that’s good.

But then what happens in say Toronto

or Vancouver in wintertime?

I guess they’re going to bed very, very early,

but also waking up very, very early.

You know, one of the things that I hear all the time,

because I’m always beating on the drum

of getting morning sunlight, even if through cloud cover,

is people say, there’s no sun here this time of year.

And forgive me, but there is sun, unless you live in a cave,

there’s sun, it’s just coming through cloud cover.

No matter where you live in the world, there’s sun,

unless you live in a cave, of course.

So I want to make sure that we didn’t overlook,

what was the major conclusion of the firefighter study?

Okay, so we’ll go back to the firefighter study.

So the reason why we did this study was, as I said,

there are a lot of us who are living the lifestyle

of firefighters or shift workers,

and shift workers are excluded from studies.

So that means whatever we are learning about lifestyle

or even medications that may be beneficial for people

who actually have a normal schedule,

but not for people who have a disrupted schedule.

And if you look up clinicaltrial.gov,

there are more than 400,000 studies listed.

And if you search how many studies are on shift workers,

it’s less than a thousand.

And then if you ask, most of them are to see

what is wrong with shift workers.

Like that’s how we know that shift work increases our risk

for metabolic disease, cancer,

and even some aspects of dementia.

But if you ask how many studies are done

to improve the health of shift worker alone,

that’s less than 50.

Means I have to go back and check the actual number,

but it’s less than 50.

So that’s why we got super excited.

We thought from circadian rhythm perspective,

that’s something to address.

So this study, again, this kind of study is only possible

because I’m at Salk and we are affiliated with UCSD

and I can work with UCSD physicians to do this study.

So I collaborate with Dr. Pam Taub,

who is the Director of Cardiac Rehab Center in UCSD.

And Pam has many firefighters as her patients.

And we both know that the number one cause

for death and disability on work for firefighters

is not fighting fire,

but just getting heart attack and stroke.

So they have a very high incidence

of heart attack and stroke,

and they’re also highly prone to different kinds of cancer.

And it may be difficult to ascribe cancer to disruption,

circadian disruption,

because they’re also exposed to a lot of toxins.

Anytime fire burns,

that smell of fire is essentially smell of carcinogens

and their breathing,

even if they have the hood on and respirator,

they still get.

So the idea was very simple.

We know that firefighters,

nearly 70% of firefighters in the US,

full-time firefighters,

because there are volunteer firefighters

and then full-time firefighters.

The full-time firefighters,

70% of them work 24 hours shift.

So for example, in San Diego,

they come in at their shift is from 8 a.m. to 8 a.m.

the next day.

And they do, at least in San Diego,

they do one day on, one day off, on, off,

four cycles and then four days off.

And, but in some fire departments,

they actually do 48 hour shift.

So they come for two days, two days off,

two days, two days off,

and then four or five days off.

Brutal.

Thank you, firefighters.

Yeah.

I mean, so then the idea was, okay,

so we’ll screen firefighters

and then find firefighters who are metabolically unhealthy.

And then we’ll see whether they can actually follow

10 hours time-restricted eating.

Because the point is, if firefighters can follow it,

then everybody else should be because,

with all that stress, if they can.

And this is again,

where I should also acknowledge

the San Diego Fire and Rescue Department,

because without their help,

we could not have even submitted the grant.

And at that time, David Picon,

who is their health and wellness battalion chief,

he’s the one who actually approached us.

Because he’s very careful.

He knew that the job that they do

makes them weaker in long-term

and can kill them in long-term.

So he was always looking for new solutions.

So he approached us and then we said, this is the idea.

He said, well, I love this idea

because we are not asking them to sleep more

or we are not going to cut down their overtime

or shift or change the work schedule.

The only thing we’ll be doing

is ask them to eat within 10 hours.

And hopefully we can do this.

Consistently between the days

that they’re working and not working?

Yes.

So that means if they’re from 8 a.m. to 8 a.m. working,

then the next day, then they go home,

then they’re gonna eat on the same schedule they did

when they were at the fire house, but while at home.

So they’re not allowing themselves to deviate from that.

Yeah, so we thought whether they can do it or not,

because the number one goal or the primary outcome

in this clinical trial was feasibility.

Can they do it?

And then second was, if they do it,

then what happens to their blood sugar and weight

and all this other stuff?

And then we started the study and we hit the next hurdle.

And that is, firefighters are a very tight-knit community.

Very tight-knit community.

And they want to make sure

that you understand their culture.

And the best way to understand their culture

is to live the life of a firefighter.

So Emily Manoogian, who is the first author,

she and then we had Adina Jadurian,

who is now in med school.

She was a research coordinator at that time.

They volunteered, they said,

okay, we’ll go to the busiest fire station in San Diego

and we’ll live the life of a firefighter.

And the San Diego Fire and Rescue and the city,

they all agreed, they reported for duty

at 7.30 in the morning.

They were assigned a bed in the station

because all fire stations do have some beds

for firefighters to rest and they have assigned beds,

so they were assigned a bed.

Yeah, so every time a 911 call came,

and if that fire station,

and that fire station, that fire engine was called,

then just like other firefighters,

they had to run, get into the gears,

adjust the shoes and a jacket and a helmet

and get into the seat and attend the call.

Of course, they won’t go to the side,

they just get out of the truck,

wait there, then come back.

So in that 24 hours, Emily got 10 calls at night

that she had to run to,

but there are more than 10 times,

they got the 911, every time the 911 call came,

then there is a beep that goes out.

All firefighters were sleeping or resting,

they’ll get up, or if they’re doing something,

they’ll look up to see which engine is called.

Interesting, so it’s not just the ones that go out,

it’s everyone gets woken up.

Everyone gets woken up.

So that means in a night, typical night,

they’re waking up 10, 15, 20 times sometimes.

So they’re almost like, you know,

new moms are like firefighters

because they don’t have any idea

what time the baby will cry

and for what reason also, they don’t know.

So similarly, so that’s what Emily did.

And then next morning, once she came back,

she was like, no.

It’s grad school, seem easy.

Yeah.

So then we did the study

and we essentially assigned all the firefighters,

we recruited 150 firefighters.

We assigned half of them to Mediterranean diet

because you cannot do any harm,

you have to give them something good.

So that’s another thing.

They said, no, we want something

that we know works for firefighters.

And there was a Mediterranean diet study, so.

So everybody was supposed to follow Mediterranean diet

and then half, nearly 75 of them

were supposed to eat within 10 hours.

We did not fix the 10 hours

because we said you pick your own 10 hours

that you can stick to.

But it has to be consistent from day to day.

So if you start eating at 9 a.m.,

you finish it at, you know, at 7 p.m.

And then try to be, yeah, try to be consistent

because we said, yes, we understand

that there’ll be some things

and you can take maybe half an hour here and there

and we’ll see how many times you can do it.

And what is interesting

was although they were all doing 24 hour shift,

they more or less chose to begin eating

somewhere between 8 a.m. and 11 a.m.

And they did not skip any meal.

They had their first meal or what we call breakfast,

but it was several hours after waking up

because they are waking up at five or six

and they’re driving to come to work at 7.30 or eight

and they’re eating their first meal,

say between eight and 11.

And then the finished meal 10 hours later.

And what we found is more or less

most of them could stick to doing this

at least five days out of seven days.

And then at the end of the study,

when we look at their health parameters,

one thing that I said, we recruited everybody who can.

So that means nearly one in three firefighters

were completely healthy.

They had no sign of any illness,

no high blood pressure, high blood sugar,

high cholesterol, depression or anything.

So since we have one third of the population

who are already healthy

and then everybody has slightly different conditions.

Some have high blood pressure,

but they don’t have high blood glucose.

If somebody has high blood glucose,

but not high blood pressure.

So it was kind of heterogeneous.

So we did not see big difference in weight loss

or any weight change between these two groups.

Another thing is the firefighters actually run

almost eight to nine miles when they’re at the job

because that’s part of their exercise routine.

But then one thing that changed significantly

in the time-restricted eating group

was what we call VLDL particle size and particle number

because this is something that we know

is very low density lipoprotein.

These are atherogenic.

And if we can manage them much better,

then we reduce the risk for atherosclerosis.

So that’s one parameter that changed

in the time-restricted eating group.

Even when you combine all healthy, unhealthy, everybody.

Now, if we take firefighters

who were beginning with high blood pressure,

then we saw a significant reduction in their systolic

as well as diastolic blood pressure.

And the change in blood pressure,

of course, we don’t claim that in the manuscript,

but when we talk about it,

some physician would get up and say,

wow, that looks like almost they’re

on a blood pressure lowering drug.

So the extent of blood pressure lowering

is equivalent to somebody taking a antihypertensive drug.

Amazing.

Yeah, and then those who started with high blood sugar,

of course, we didn’t have too many type two diabetic,

but there are a few pre-diabetic

and they could better manage their blood glucose.

And this is interesting because once shift workers

become pre-diabetic or diabetic,

they have more difficulty managing their blood sugar

than non-shift workers

because the work schedule itself

will mess them up too much.

Even if they’re on many medication, they have difficulty.

That’s fascinating.

And I’m really glad that you explained the study

in such detail,

because I would have thought from reading the abstract,

and I did look at the data,

but if someone were to look at the abstract,

they’d say, oh, firefighters,

so they’re waking up in the middle of the night

and they’re throwing on their gear

and going out to calls and do it.

But if I understand correctly,

all firefighters are being woken up by the signal,

which makes the firefighter population

a bit more similar to the more standard population

who’s waking up in the middle of the night

to use the bathroom,

getting on social media for a couple of minutes

or flipping on the lights.

I mean, it’s maybe not as severe

as what firefighters are doing,

but we know there are blood sugar regulation issues

related to those multiple middle of the night wakings,

especially if people are then staring at screens.

So I think it’s really important

that people were able to hear

about the deeper contours of the study.

I mean, this result of regulating blood sugar better

is really powerful.

I get asked all the time, you know,

I’ve got a new kid or I’m a shift worker.

How can I do this morning sunlight viewing?

What I’m hearing is that

keeping a regular meal schedule every day.

At least five out of seven.

Five out of seven, or as close to every day.

It’s sort of like sleep.

I always say, try and get a really great night’s sleep,

80% or more of the nights of your life.

And on the other 20%, hopefully it’s for fun reasons,

a great party or something like that,

or a celebration of some sort.

That seems to me a great anchor point

when one can’t reliably control their sleep-wake cycle.

Does that mean that if somebody is coming off of shift work

and they’re very, very tired,

that they would be better off staying awake and eating

than sleeping?

Well, yeah, so this is where we get into nuances.

So here, the firefighters are 24-hour shift workers.

So that means, and they have been working the shift

for a very long time, so they have figured out.

And one thing is, yes, firefighters are different

from nurses and healthcare workers

who have to work throughout the night

and they’re staying awake throughout the night.

Whereas firefighters, they get opportunity to sleep.

Then even with their pen calls,

they actually have opportunity to come back and go to sleep.

And in fact, when Emily and Adina,

when they were in the fire station,

what they observed was firefighters,

after attending a call,

they’re not coming back and playing cards

or trying to watch the news or get the score.

They know, they will just go back and lie in the bed

and switch off the light.

So whenever they got any opportunity to sleep,

they would try to sleep.

So in that way, their sleep debt and sleep pressure

during daytime is not as strong as a night shift nurse.

Or a truck driver who is driving all night

because they are staying awake throughout the night.

So when people say, yes, you found this

and can you extend it to other shift workers?

My answer is no, we have to go back and figure out.

That’s why we went to the station

and figured out what would work for them.

If I have to go and do this for some nurses,

maybe even I will go or our staff will go and figure out

what is their work schedule?

What happens?

Do they have opportunity to eat?

Do they have opportunity to even take five minutes break?

What do they do during break?

And all of these things come into play.

But here, another thing is,

I always said that in other time-restricted feeding paper,

we see change in nutrition quality and quantity.

But here, we also saw that somehow both groups

inadvertently, they improved their nutrition quality

because everybody was told to eat Mediterranean diet.

They increased their fruits and vegetables

and olive oil intakes slightly.

And when they had to stop eating early,

they also reduced their alcohol intake.

And this is very significant because many shift workers,

just to cope with the shift work,

they tend to depend on alcohol at night

and caffeine in the morning.

So they begin their day with caffeine and end with alcohol.

And now we can relate that many normal people

who are not doing shift work,

we also more or less begin our day with caffeine

and many of us end with alcohol.

And then when they reduce that eating to 10 hours,

and then we saw a significant reduction in alcohol intake

in the time-restricted eating group,

but not in the standard of care or Mediterranean diet group.

I certainly support that.

We did an episode on alcohol and I was shocked

when I researched that to learn that zero

to two drinks per week is essentially the threshold

beyond which you start seeing health deficits

in particular cancers and metabolic disruption,

sleep disruption, and increased anxiety

when people aren’t under the influence of alcohol.

I mean, it’s pretty incredible how alcohol

has kind of escaped as the opposite of caffeine

and therefore not a health hazard.

And here I’m somebody, I have a drink every once in a while,

no big deal for me, I can have it or not have it.

But it’s just striking how alcohol,

despite extensive data that it can really disrupt health

even at three drinks per week is just avidly consumed

as if it was kind of like food or caffeine.

It’s really incredible.

I wanna make sure that I circle back

to something you mentioned earlier

because I know there are going to be a number of people

that ask this.

If I recall, you said that provided

that the feeding window is not shorter than eight hours

that men, women, and children

can use time-restricted feeding.

Is that right?

Yeah, so what I say is 12 hours.

Excuse me, 12 hours.

Thank you for that clarification.

Because we did a study that was published in 2015.

And again, behind many of our studies, there is a story.

So we are publishing all these mouse stories

and then I would go to conferences.

And then, of course, some people would give me a look

saying, well, you must be doing something wrong.

This just breaks the X law of thermodynamics

because how come they’re eating the same number of calories

and not gaining weight?

Of course, by that time, we figured out that,

at least in mouse, time-restricted feeding

also changes the gut microbiome in a way

that the mice may be pooping out a little bit more fat

and sugar than absorbing them.

So one thing that happens in time-restricted feeding,

at least in mice, is their liver cholesterol metabolism

to bile acid and bile acid excretion in the gut changes

because the gut microbiome changes.

So this is a very nice study.

When Amir Jarinpar was in the lab,

now he has his own lab in UCSD,

and he meticulously did that.

And we even did bum calorimetry from the poop

and metabolomics from the poop.

And then we figured out that they excrete some calories

and then their brown fat activity goes up.

So they may be burning some of these extra calories.

So they’re more thermogenic.

More thermogenic.

But anyway, so one nice thing, awesome thing about Salk

is if they see that your science is going well,

then they will find ways to help you.

And this is-

That’s terrific.

Yeah, and this is when Bill Brody was our president.

He was the president of Hopkins for 12 years

and then he was president.

And that time he had started this innovation grant program,

which was funded by Orwin Jacob.

Orwin is the founder of Qualcomm.

And he was also a faculty at UCSD.

So he understands there are very few tech leaders

who actually spend some time in academia.

So he understood the pain of getting grant money

when you have some interesting idea or test some ideas.

Yeah, no knock on the NIH, but I’ll do it anyway.

Because I sit on study section for the NIH.

I mean, the NIH wants to see proposals

for things that are so certain to work

that they’re mostly done.

And so really groundbreaking work can happen

and does happen with NIH funding,

but more often than not,

it is the generosity of philanthropists like Orwin Jacobs

and other people that allow the really pioneering,

the new stuff, the cool stuff, the groundbreaking stuff,

the stuff that really, no, I’m not gonna say really matters.

It all matters.

It’s all important.

No, it matters, but it’s high risk.

And NIH means NIH is not just government

is not making money from thin air.

It’s taxpayers’ money.

So there is a little bit responsibility or conservative

that, okay, so we should not waste taxpayers’ money

on pie-in-the-sky kind of project too much.

To be clear, we’re not talking

about politically conservative.

We’re talking about scientifically conservative.

They’d be so careful with language nowadays.

Pretty soon, we’re just gonna sit and stare at one another

at the microphones to stay safe.

So that’s interesting.

So then we started this.

And then what we did was we,

I had an awesome grad student

and we got this funding from Irwin.

And also there are some, any philanthropy matters.

So actually the way we say is, yes,

if you give me 50 bucks,

then that 50 bucks goes towards buying the gloves

and a friend of tubes for one postdoc for maybe seven days.

So true.

I think a lot of people don’t realize

that 99% of laboratory scientists,

just they don’t make any money off their discoveries.

And even if there is a patentable discovery,

typically the divide between the institution

and the company that will eventually put that to market

is so slim in favor of the others involved

that scientists really do this as a work of passion,

labor of love.

So we came up with this app, MyCKDnClock at that time.

And we took some lessons from tech leaders,

particularly from Amazon One Click Checkout,

because we thought most nutrition apps

actually ask people to detail, describe what they ate,

go to their food library and then portion size.

We said, okay, so we’ll just shortcut all of that.

We just ask people to take a picture of the food,

open the app, one click,

take a picture, second click,

and press save, third click.

And when they saved, the picture actually came to our server,

did not stay on their phone.

And we asked 156 people who are not shift workers,

just regular worker or homemakers,

to be part of the study.

No student was allowed to be part of the study

because we know that their lifestyle is like shift workers.

And we monitored for three weeks.

And so here is some nuances,

and I want people to understand.

So suppose when somebody is starting to eat

at say 7 a.m. and since they’re recording everything,

we caught every single thing.

Even if they ate half a cookie,

they had to take a picture,

and they actually took picture because it’s not,

it becomes second nature after three or four days

that every time they ate something,

even if there was a glass of water,

they actually took a picture because we asked them,

take picture of everything, we’ll figure out what it is.

What is surprising was we found the median,

so the median number of times people eat

within a day, 24 hours a day, is actually seven.

So it’s not that we are eating three times a day,

we actually snack a little bit.

Seven times per day.

Seven times.

And there are 10% of people,

the top decile was eating 12 times a day.

Wow.

And it makes sense in retrospect sometimes,

maybe I’ll fall into that seven or eight

before I did this study.

Getting up, having coffee with cream and sugar is one,

and then I ate my breakfast, that’s two,

then I came to the lab and I found that cookie,

that’s three.

I went to a meeting and there was some cookie

and something else, that’s another one,

then lunch, and then afternoon somebody asked me

to go out and have a meeting.

So if you think about it, it’s very normal

that we can go seven to eight times, 10 times.

But then, if we look at what time, say I start breakfast,

and as I said, we see that in many people,

they’ll start at seven o’clock one day,

then 7.30 another day, then 8.15 another day,

or they go back to 6 a.m. because they had to get up early

and go to work.

So we took all these food data from three weeks

and then asked, what is the time when your body’s system

is expecting it to eat?

Because it’s kind of averages out,

it’s kind of thinking, okay, maybe for you,

if you’re eating breakfast at say somewhere

between 6 a.m., 7.30, 7.45, 8,

maybe you are expecting food around seven o’clock.

Let’s forget about 6.15, that’s an outlier.

And then similarly, at the end of the day,

if somebody is eating, finishing the last bite

or the night gap, whatever you call it,

say one at 9 p.m., 9.30 p.m., 10, 11, 12.30, or one,

let’s ignore that one and 12.30,

but still we got somewhere between seven to 11.30

for that person over three weeks time.

So this is how we kind of figure out

what is the likelihood that your body will encounter food.

So when we do that, what we found was nearly 50% of adults

in our study ate for 14 hours, 45 minutes,

that window when your body is expecting food.

So it’s easy to say that 50% of adults

are eating within 15 hours or longer.

Wow.

And quite frequently throughout that period.

Quite frequently too.

And then if we asked what fraction of our adults

were actually eating the conventional within 12 hours,

three meals a day or something like that, it was 10%.

So these-

So snacking has gone up dramatically,

however you want to define snacking,

the frequency of food intake throughout the day.

And outside this breakfast, lunch, and dinner,

there are all these small snacks here and there.

And also for a lot of people, the dinner is delayed.

And we went back and looked at, okay,

so what kind of food people are eating late at night

and all that stuff.

And what came out interesting,

which is very counterintuitive,

is people who prepare their own dinner,

they’re more likely to eat later at night

because they’re coming home

and then they’re taking some time to prepare dinner.

And then they’re sitting down and eating,

or maybe they’re eating next to the computer,

whatever it is.

So it was kind of interesting that came out.

But coming back to your point,

that’s why I say that nearly 90% of adults

are eating for more than 12 hours.

So that means a lot of people can,

there is scope or there is enough headspace

to reduce and eat within.

So as I said, all of this are interrelated.

So when you think about children,

most sleep researchers agree that children and teenagers

should sleep somewhere between nine to 10 or 11 hours

because young children, even five to 10 year old,

they should sleep nine to 10 hours.

They’re just pumping out growth hormone

and growing, growing, growing.

And then the teenagers, actually the recommendation is

they should be sleeping nine hours

because if you take teenagers,

take out all the stimulatory inputs to them

and then remove homework assignment and everything,

and then let them kind of equilibrate

to their homeostasis, what they’re likely,

how many hours they’re likely to sleep,

that turns out to be somewhere between eight and a half

to nine and a half hours,

which also means that going back to sleep,

nearly 90% of high school students in this country

are chronically sleep deprived

because most high school students don’t get nine hours

of sleep on a regular basis, maybe in the weekend.

Probably because of devices.

Yeah.

They’re on iPads and phones.

And also, as I said, this new idea

that midnight is your assignment submission time.

I’ll come back to that again and again.

I’m hearing that again and again, so teachers take note.

It’s a very interesting idea as a way

to kind of anchor behavior earlier in the day.

Yeah, learning to, I mean, public health is complicated

because people are incentivized by fear,

but you get more bees with honey, as they say, right?

You know, there’s incentivizing people to wake earlier,

not necessarily with the sunrise,

but wake earlier and go to sleep earlier

and eat within an eight to 12 hour window.

12 if it’s children.

Yeah, so that’s why I said, yeah.

It sounds to me like, you know,

all these health benefits are what I think

are going to incentivize people more than,

for instance, this idea that, well, if you don’t do this,

you’re going to get dementia or something of that sort.

No, no, exactly.

Right.

People will feel more healthy and more productive.

And so that’s why I said that even if children

are supposed to sleep for nine hours,

of course they’re not eating during those nine hours,

and we’re not feeding children

and putting them down to sleep

because their core body temperature will be high,

they cannot fall asleep.

So at least they should have their last meal

one or two hours before going to bed

because typically parents feed them

and maybe give them a shower or a bath,

and then they read the bedtime story.

So it’s one to two hours before bedtime

they’re finishing food.

Similarly, on the other end, after they wake up,

it’s not that we are waking them up and then feeding them.

Hopefully we’re not doing that.

So that’s why 12 hours seems to be optimum.

And it’s not only, I’m saying that

if we put all the health recommendations together

from pediatricians, then it makes sense.

Fascinating.

I have a question about structuring meal intake

or food intake during the eating window.

I have a good friend, actually he’s the neurosurgeon

at Neuralink now, but he came up through Stanford

and he has a habit of skipping one meal per day

within a feeding window.

So it might be breakfast, lunch, skip dinner one day,

then it might be breakfast, dinner the next day,

lunch and dinner the next one.

So it’s not in keeping with the same start time always,

but the end time is either gonna be earlier

or there’s a gate, it’s never later.

It’s never later.

What do you think about that as a strategy?

You know, in many ways, it feels like that fits

with the way that a lot of people’s lives run.

So sometimes, for instance, if I’m in a podcast,

I don’t tend to eat much during the middle of the day

because it makes me a little bit groggy,

the post-parendial dip in energy.

So I’ll do breakfast, well, again, at 11.

And that’s the first, that’s when I break my fast, 11-ish.

And then dinner, maybe a snack in the middle of the day,

but other days it’s three meals.

So does it matter overall,

as long as one isn’t allowing the start time

and the ending time to drift out?

Is it okay if you go from 12 hours to 10 to eight,

eight, 10, four, 12,

as long as you don’t exceed the brackets, are you okay?

So this is where the circadian aspect come in,

because if you’re going,

if you’re moving that breakfast time or dinner time

three, four hours, you’re essentially causing

maybe a metabolic jet lag.

You know, in short term, in weeks, months,

or maybe even a few years, you may not see any change.

But at the same time,

we don’t know what are the long-term consequences.

One thing is we always think,

I’ll come back to this point again and again,

we think that our body weight is a marker of health,

or body composition is a marker of health.

It’s not always true, because as I said,

acid reflux, feeling, you know,

having some pang of depression or anxiety.

Or LDL, like high LDL.

High LDL.

A lot of thin people have,

or low body fat people have very high LDL.

Yeah, so those are the things

that we don’t connect with our habit.

And since circadian rhythm and meal timing,

meal structure now is a very new field.

I think good studies will come out only in a few years.

Because right now people are just going back

and retrospectively looking at some diet record,

one day of diet record,

and trying to glean too much out of it.

But I think hopefully things will improve

where people will become,

it will become standard to at least look

for one week of diet record.

Mealtime and what they’re eating, all that stuff.

Because there are now mouse studies also showing

whether front-loading carbohydrate,

or front-loading fat, or protein has benefit over.

So I think these studies are starting.

So I should not comment whether that’s good or bad.

I think it’s great to hold off

until then we have you back on to discuss.

I have a question about fasting on the longer term.

And there, it’s a near infinite space we could explore

of two days of fasting.

I know people that every once in a while,

they just decide I’m fasting.

They’ve either been eating too much at parties,

or they’re not feeling well, or whatever.

They just decide I’m fasting for 24 hours.

And they’ll still consume water and caffeine,

but they’ll just fast.

Is there any health benefit or detriment?

You mentioned the circadian clock shifting effects.

But if somebody wakes up on Sunday

and they ate too much, or they feel they ate too much,

or they don’t like the food they ate on Saturday,

they’re not really feeling it.

And they’re just gonna fast into Monday.

Is there any known benefit or health detriment

to doing that kind of thing?

Yeah, there’s actually a rich literature

on this complete fast.

And in fact, in many religion,

people practice complete fast as a way to cleanse their body

and people have seen that there are benefits to that.

So in fact, the every other day eating in mouse model,

or even in humans that are also initially

some studies were done, there are many health benefits.

And right now there are even fasting clinics in Germany

where people check in and they’re under strict supervision

and then they do complete fast

or maybe a small bowl of soup, which has 100, 200 kilocal.

And that’s all they get to eat.

Sometimes two, three days, four days, five days,

even they have gone up to three or four weeks.

For sake of weight loss, is that why?

For many different things.

And they come out pretty well healthy.

Of course, they’re under supervision,

make sure that they’re getting the micronutrients,

vitamins and electrolytes.

So those studies are pretty solid.

People have observed that.

And then in fact, there are even idea that fasting,

this kind of fasting can have huge impact on brain

and people may come out of treatment resistant depression

or something.

So those studies are very difficult to do.

They’re only case of one here and there

that we hear once in a while.

But hopefully in future, we’ll see whether the depression,

anxiety, the mental health aspect will benefit from fasting

because now as there is more and more evidence

that there’s this gut brain axis

and what are the presence of food

or the microbiome changes in the gut.

If they can affect brain, then maybe long-term fasting,

periodic fasting, a few days of low calorie diet

back to back will be interesting to see

how it impacts brain health.

Very interesting.

What are your thoughts on fat fasting?

Where people try and limit their blood glucose

by only eating mainly fats, mainly healthy.

Typically they’ll eat healthier fats.

So avocados, olive oils, and nuts and some animal fats

perhaps, but as a way to keep blood glucose low

and also time restrict.

This goes back to the kind of low carbohydrate thing.

What are your thoughts on that

as a general strategy for health?

I mean, it combines sort of two general themes

that are out there.

I think both of which are data are still incoming

that restricting the feeding times, it can be beneficial

as well as keeping overall blood glucose lower

can be beneficial.

Yeah, I think there is too much emphasis now

on blood sugar spiking or we don’t know

this kind of eating pattern, for example,

means we are essentially telling pancreas that, okay,

it’s the islet cells that produce insulin.

It’s okay, you can take a break, go on vacation

for a month or two or three months.

My question is, it’ll be interesting to see

what happens to those islets, because for example,

we know that if we disuse or unuse our muscles,

there’s muscle atrophy, muscles will become weaker.

We don’t know whether long-term consequences

of this very low carbohydrate diet

where you’re not essentially engaging the islet cells

periodically, what is its impact?

So if there is no impact, maybe it’s okay,

because as you know, many people who actually work

on ketogenic diet, the researchers themselves,

they find it very difficult to stay in true ketogenic diet

because the true ketogenic diet is consuming

less than 10% of calories from carbohydrate.

And not very many from protein.

A lot of people think ketogenic diet allows them

to eat massive amounts of meat,

and that’s not necessarily the case.

Just one clarification for people,

Sachin was referring to islet cells of the pancreas,

which are the ones that manufacture insulin.

So the question is whether or not taking in low levels

of blood glucose by way of a low carbohydrate diet,

those islet cells are going to shut off their production.

Very interesting, I mean, the liver’s a very plastic tissue.

I mean, it tends to react very dramatically

to lifestyle changes.

Yeah, so that’s why it’ll be interesting

to see what happens, means we know that even muscle disuse,

for example, people who become bedridden,

they lose some muscle mass, but when they come back

and exercise, they gain it back.

So it’ll be interesting to see what happens

in these people who are going through

a long-term ketogenic diet.

And of course, once in a while,

because of social pressure or something else,

if they don’t have access to food or something happens,

they may consume some sugar,

some blood glucose will spike,

but it’s not that every spike is bad.

I mean, the reason why we have insulin is for good reason.

To buffer that spike.

To buffer that spike, and also, you know,

people always say that, well, if you have insulin produced

or insulin-like growth factor, those are really bad,

and you should avoid that.

And I think that’s a little bit extreme, and-

I mean, the insulin growth factor

has evolved in muscle protein synthesis,

tissue repair, maybe even cognition.

And it also goes back to, say, mTOR activation

and all that stuff, people get really excited

about how to reduce mTOR activation,

rapamycin and all that stuff.

So this is where, again, from circadian point of view,

I ask people to think.

So two very popular drug-like molecules or drugs

that people think will increase longevity are metformin,

which many people agree, not all will come to a consensus

that it activates AMP kinase, or the sensor in the cells

that sense that your cells are fasting.

So metformin kind of activates it so that it kind of,

you can say, although it may not be scientifically accurate,

the, you know, fasting in a pill.

So it sort of mimics fasting.

Yeah.

And the thing I’d lump in there with metformin

is that berberine is kind of the poor man’s metformin.

It’s a tree bark extract

that also dramatically lowers blood glucose.

Yeah, and it mimics kind of that fasting.

And then rapamycin also kind of reduces mTOR activation.

And people have shown that rapamycin and metformin

can extend mouse lifespan and improve health.

Okay.

So now let’s go back to the calorie restriction study

that I mentioned.

In calorie restriction, people are giving food as a lunchtime

and they were essentially doing time restriction.

The mice were doing time restriction.

If we think about it, during daytime,

when experimenters are coming to the vivarium,

the mice should be sleeping and fasting.

And they should naturally have high level of AMP kinase

if they’re truly fasting.

And they should also have low level of mTOR activity

because mTOR responds to insulin

and that should go off at night.

So my suspicion is in many of these experiments

where the mice were allowed to eat ad libitum,

even normal standard chow,

now we know that as mice get older,

they actually consume a little bit more food during daytime.

Which is the equivalent of human nighttime.

Human’s nighttime eating.

It’s like nighttime eating we know is an issue.

I didn’t realize that was more of an issue as people age.

Yeah, so we don’t know, but at least in mice,

because we can put the mice in calorimetry,

look at every single bite they’re eating,

how much they’re eating.

So I guess it was natural to see that researchers found

that there is some mTOR activity during daytime

when the mice were not supposed to have mTOR activity

because they should be fasting.

And since they ate a little bit,

they were snacking during daytime,

AMP kinase activity was not at its peak.

So giving metformin kind of mimic their fasting state

and reducing mTOR activity by drug like rapamycin

also kind of mimics some aspect of the fasting state.

So my suspicion is since these studies were done

always in mice who are supposed to be in the fasting state

and both mTOR, sorry, rapamycin and AMP kinase activity

or metformin kind of are mimicking that fasting state,

that’s why we have seen those benefits.

And it’ll be interesting to see if that experiment

will be done in humans in the long term

because many people are very excited about,

you know, there is mTOR long-term metformin study

and then a lot of people are actually consuming

good amount of rapamycin off level, they can get their own.

So that’s my curiosity.

I’m not saying whether it’s good or bad

or whether there is science or not,

that’s something that will be interesting

to control for and see.

Because recently I saw one of my, again,

close friend and colleague at Scripps, Katya Lamia,

she did a very simple, elegant study

people should have done in metformin field.

And she took mice and then measured their blood glucose

at different time of the day.

And in fact, just like human blood glucose,

our blood glucose fluctuates a little bit.

She saw that rhythm.

And then in every two hours or three hours

on different days, of course,

she gave the same dose of metformin to mice.

And what she found was at different time of the day,

metformin had very dramatic change

in glucose reducing ability.

So which means that even if you take metformin

and give at different time of the day for the mouse

or even for humans, in very long term,

of course, in these mice,

and these mice were not diabetic or anything,

they were healthy mice to begin with.

So in long term, we might see benefits

that are very different.

So this brings to this idea that,

well, maybe metformin, say, at the end of the day,

evening metformin may trigger that fasting state

much earlier than end of digestion.

Whereas metformin in the beginning of the day may not,

at least from longevity perspective,

I’m not talking about type two diabetes here.

So the same thing with mTOR.

Is mTOR going to have much better impact

if taken during evening, morning, before meal?

So these are my thoughts that go along

with all this fat story that we talked about.

Do you take metformin or Berberine?

No, I haven’t taken.

Although, you know, I have close friend and colleague,

Ruben Shaw, who is now the director

of Cancer Center at Salk.

He extensively works on AMP kinase and its mechanisms

and so it’s always fun to talk to him.

He’s a fan.

Yeah, I’ve taken Berberine before

and I’ve had two different,

very distinct experiences with them.

First of all, Berberine, when ingested with carbohydrates,

in particular carbohydrates that have a lot

of simple sugars, definitely,

I know this because I measured my blood glucose,

I did the experiment,

allows you to flatten out your blood glucose response.

So, you know, in some sense, if you’re, you know,

there is this idea, if you’re going to eat

a particularly big meal or sugary meal

and you don’t want to get a massive blood glucose rise,

you take Berberine or metformin.

Metformin is prescription, that’s why I went with Berberine

because as far as I know, it works as well.

At least for healthy people.

Yeah, for healthy people, that’s right.

When I took Berberine and did not ingest large amounts

of simple sugars or carbohydrates along with it,

I experienced profound hypoglycemia.

I felt like complete garbage for about eight hours.

And I had one of the worst headaches of my life.

Because, which makes sense,

you just got a blood sugar crash.

So if you lower your blood sugar

when you already have fairly low blood sugar

and you’re not ingesting carbohydrates,

you can really bottom out your blood glucose.

So just say it’s, I say that as a, for two reasons.

One is kind of a cautionary note.

And the other one that when you think about the biology

of these compounds, it makes perfect sense.

And I think that, and I did not pay attention

to the circadian effects.

Yeah, yeah, yeah.

I mean, it’s, you know, when I joined Salk around that,

we know Ron Evans is the kind of the big leader

in metabolism and he works on nuclear hormone receptors.

These are the master regulator of metabolism

in normal cells, cancer cells, and many other.

And what was interesting was in the first few years,

Ron did a very simple experiment.

He just looked at what time of the day

this nuclear hormone receptors are turned on

at gene expression level and some at protein level.

And he found that almost all of them

have a circadian pattern, at least in some tissue.

So he went to that length to say even

that circadian is metabolism and metabolism is circadian.

The reason why we have a circadian rhythm

is to have a daily rhythms in food seeking behavior

and eating, and also go through a period of time

when we should be fasting.

And then on the other hand, all the metabolic regulators

also have to follow that rule.

And almost all metabolic regulators,

everything that we can think of connected

to metabolizing macronutrient, protein, carb, and fat,

they should also have a circadian rhythm

or diurnal cycle to align or misalign.

So for example, fat oxidation should be

in opposite phase with feeding.

And in retrospect, at that time,

it was kind of amazing to see Ron could foresee,

of course, he’s smart enough to foresee

and predict that this is going to happen to circadian period.

Because at that time, we’re thinking

about the suprachiasmatic nucleus, sleep-wake cycle,

and we are not thinking too much about metabolism.

So that’s the awesome thing about Salk, being at Salk,

because we have 50 PIs really crammed

into two awesome buildings and with open lab structure.

So you bump onto each other and talk to each other.

And with an ocean view.

With an ocean view.

Yes, it’s an amazing place.

I was lucky enough to have an adjunct position there

when my lab was at UCSD, and it is an amazing place

doing incredible groundbreaking work,

which of course includes yours.

Sachin, I’m clear now that we have to have you back on

for another series of discussions, seriously speaking,

if you’d be so kind and willing to do that.

I want to thank you for several things.

First of all, for taking the time today

to sit down and discuss these incredibly interesting ideas

in detail.

Much of what we talk about on the podcast

is obviously grounded in science and often,

but not always is actionable.

And so much of what we talked about today is actionable

in the sense that many people are already doing

certain dimensions of these things.

Some are not, some are hearing about it and considering it.

You’ve given us dozens, I’ve listed some out,

dozens of tools and considerations

based on whether or not people are engaging

in shift work or not.

I think a lot of people are going to realize

that they are shift workers,

even though they didn’t think they were

because of the nature of their habits now

to light and to activity and so forth.

I absolutely love the firefighter study

because of its relevance to the general population.

Also another nod to firefighters

and shift workers everywhere, thank you.

And I think among the colleagues I’ve known

for several decades now,

you really are one of a very small few

who’ve managed to do both animal studies and human studies,

but also animal studies with a very clear eye

and a pointer toward human health.

And that’s such a vital and rare thing,

especially in this day of extremely competitive funding.

So I want to thank you for your time today,

for the knowledge you share,

the actionable aspects of that knowledge,

the science that you’re doing in your laboratory.

We will provide links for people to learn more about you

and of course to go to the app

so people can engage in some of the science directly.

And of course you have several wonderful books now

that we will also link to,

both of which I’ve read and are wonderful,

in particular the first book,

but also a book related to diabetes.

And so for diabetics and people interested in metabolic

and blood sugar regulation there.

So on behalf of myself and my team here

at the Huberman Lab Podcast and all the listeners,

I just want to say thank you so much.

Your time is valuable.

And the fact that you share it with us

and educate so many people is really a gift.

Yeah, thank you.

And actually likewise, there are very few scientists

who have taken this leadership role that you have taken

to come and communicate science to the public.

It’s not easy because sometimes you have to distill it down

to a simple soundbite to the point where the scientist

and they’ll say, oh, that may not be right.

But we always have to keep in mind

that we are always living in the dark age of science

because the reason why I say that,

this is not my quote actually,

this is from one of my scientific hero,

Paul Simmel from Scripps.

He always says, think about it.

10 years ago, what you thought was right

and the best has already changed.

But one thing is the circadian rhythm

and aligning it to our internal clock

to our habit is very important.

And as you mentioned, we have our My Circadian Clock app,

which is research facing,

but we have also distilled all of this

down to five or six timing component.

And we have a new app called On Time Health

or Get On Time Health.

Can people access that through the standard app stores?

Yeah, so now it’s available in Apple App Store.

And we want to see how,

because people always think about fasting,

but as we discussed today, feeding fasting

or eating fasting and activity and sleep,

are kind of interlinked

and we have to kind of balance both of these.

So that was the idea behind this On Time Health program.

And thank you, Andy,

because what you’re doing is immensely necessary,

particularly these days when science

is moving at a very fast pace,

there are a lot of results coming out.

Sometimes something can be very confusing

and you spending your time to communicate science

is exceptional.

So thank you, Andy.

You’re most welcome.

It’s days like today where I get to sit down

and talk to brilliant colleagues like you

who are doing the important work

that really matters so much.

And so, as you mentioned a moment ago,

that there’s a lot of darkness and confusion out there,

but thank you for being one of those who’s shining light.

Thank you.

Thank you for joining me for today’s discussion

with Dr. Sachin Panda,

all about circadian biology and time-restricted feeding.

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Thank you once again for joining me

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I hope you found the conversation to be as informative

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And last, but certainly not least,

thank you for your interest in science.