Dr. Satchin Panda on Time-Restricted Feeding and Its Effects on Obesity, Muscle Mass & Heart Health

Dr. Satchin Panda on Time-Restricted Feeding and Its Effects on Obesity, Muscle Mass & Heart Health

August 5, 2019 100 By William Morgan


[Rhonda]: Hello, everyone.
Today my guest is Dr. Satchin Panda, who is
a professor at the Salk Institute for Biological
Studies in La Jolla, California, where he
studies the body’s internal circadian clock,
what regulates their circadian clock, and
in turn, how this affects a wide variety of
processes including our metabolism, our sleeping
patterns, and how active we are, and so much
more.
Satchin, considering that every single living
organism on the planet Earth has this internal
biological clock, their circadian clock, can
you explain to people who’ve never heard what
a circadian clock is, what it is and why it’s
so important?
[Satchin]: Yes, so all lives on this planet
evolve under a rotating Earth.
So that means for 12 hours, approximately
12 hours they had access to light and for
another 12 hours they were in darkness.
So, that environment, that changing environment
put a tremendous pressure for them to come
up with a timing mechanism so that they can
anticipate when it’s going to be evening or
when it’s going to be morning so that they
can time their activity and sleep accordingly.
So that’s why almost every organism on this
planet have this internal clock that help
them anticipate time.
And why this is important is if you think
about a diurnal organism, an animal that’s
active during the daytime, the animal has
to anticipate when evening is going to come
so that he can rush back to the cave or somewhere,
some hiding place.
So similarly, just before the dawn, this animal
has to wake up before even light hits, and
then go out and get the first grub.
So that’s why there is this tremendous pressure
to have this biological clock or internal
timing to essentially anticipate what is going
to happen.
So for most people, we know when we go to
bed, maybe after six to eight hours, we wake
up.
So our clock actually tells us, “Yes, it’s
going to be morning.
Get up now.”
So similarly, almost every part of our body
has clocks that help us to anticipate when
the food is gonna come or when we are supposed
to run, when we are supposed to take rest.
So, what we are learning is almost every organ
in our body has a clock and it helps this
organ to be at peak performance, peak activity,
at certain time of the day, and then to rest
and rejuvenate at the other time of the day.
[Rhonda]: So, is this internal biological
clock, the circadian clock, it’s not something
that we’re just immediately born with, right?
It’s not something that just…
[Satchin]: Yes.
So when we are born, we, kind of…when babies
are born, they actually don’t have this daily
24 hours rhythm in activity or sleep.
They don’t to bed for six or seven hours.
So what we suspect is although they have a
clock, those clocks are not wired together.
And at the same time, babies also need a lot
of food, because that’s their growth phase.
So, during the first maybe four to six months,
the babies wake up in every three to four
hours, cry, eat a little bit, and go back
to sleep, and then wake up again, and do that.
Then after 8 to 12 weeks, they actually begin
to have some kind of consolidated sleep.
So they go to sleep and wake up at the right
time, wake up after a few hours, but it’s
not tied to light-dark cycle.
So they kind of drift.
So that’s the phase many parents may not notice
because we now live in a very artificial environment,
but that’s the time when there is a clock
but it’s not tied to outside light and dark
cycle.
So around six months of age, that’s when the
whole development process and the clock is
functional, it’s tied to light-dark cycle,
it’s wired properly, so the babies go to bed,
hopefully, in the evening and then sleep for
nine to ten hours, wake up.
So when we are born we do have clocks, but
they are not connected together until about
four to six months of age.
[Rhonda]: Oh, interesting.
And you mentioned…so there’s, there’s clocks
in all of our organs and there’s different…your
work, you’ve done a lot of research on what
regulates these different clocks.
[Satchin]: Yeah.
[Rhonda]: There’s a master regulator clock,
and there’s other clocks in different organs.
Maybe you can explain.
I read somewhere that something between 10%
to 15% of the entire protein-coding human
genome is actually regulated by these circadian
clocks, and anywhere between around, like,
40% to 50% of those genes are actually involved
in metabolism.
[Satchin]: Yeah.
[Rhonda]: So, there’s, there’s a wide variety
of processes that are regulated by these clocks.
[Satchin]: Yeah.
[Rhonda] Maybe can you explain a little bit
about the central master clock and…
[Satchin]: Yeah.
[Rhonda]: …what regulates that?
[Satchin]: [laughs] Yeah.
So this is a field of study that is actually
not driven by a disease but pure curiosity.
So for a long time, people thought that there
might be a master clock in the brain because
we always connect circadian clock to sleep-wake
cycle.
And fortunately, there was actually a master
clock.
And in fact, almost 40, 45 years ago, people
who are working on different parts of the
brain…because at that time, 40 years ago,
people thought that different parts of the
brain regulate different behavior.
So they are defined like cubic millimeter
area of brain that regulates something.
So we’re systemically taking out parts of
the brain in mouse, rodents, and different
larger rodents, and then figure out that when
they hit this small part of the brain called
suprachiasmatic nucleus, so that means we
know that our eyes send optic nerves that
crisscross and there is a part of the brain
called optic chiasma, so it’s above the optic
chiasma.
So that’s why suprachiasmatic nucleus.
So that’s…
[Rhonda]: Say that 10 times fast.
[laughs]
[Satchin]: Yes [laughs].
Suprachiasmatic nucleus or SCN, it’s composed
of around, say, 100,000 neurons, I guess,
in humans, really small, maybe one millimeter
by one millimeter.
That’s the size of this brain part.
If you remove that brain part in a hamster,
then this hamster doesn’t, will not have any
sense of time and go to sleep at random time
and will wake up after two or three hours
and it continues.
But what is most exciting is if we take SCN
from another hamster and transplant, it’s
like a brain transplant experiment, then this
hamster will get all the rhythms back.
That’s the earliest example of neural transplant
transferring behavior from one animal to another
animal.
And that essentially established that there
is part of the brain that accesses master
circadian oscillator or circadian clock because
it orchestrates this daily rhythm in waking
up and going to sleep.
And just imagine, only when we are awake,
we eat, or we exercise.
So that’s why all other organs related to
eating, for example, our gut, our liver, our
fat, all of them are driven by this feeding
behavior.
Similarly, our muscle is driven by when we
run.
So that’s how the SCN acts as the master circadian
oscillator.
So if we damage the SCN then we lose all circadian
rhythm.
So what happens in some of the neurodegenerative
disease, like very advanced stage of Alzheimer’s
disease dementia, if the SCN, this part of
the brain is affected, then people lose their
sense of time in terms of when they go to
bed or when they stay awake.
So this presents slowly, they turn into a
state where they don’t have a sense of day
or night.
They stay awake throughout the night and may
be sleepy throughout the day.
So that’s why this master clock is so much
important for our health.
[Rhonda]: And that might also have a feed-forward
loop because then, you know, if your master
clock is thrown off and you’re awake when
you’re supposed to be sleeping and sleeping
when you’re supposed to be awake, that’s also
been shown to affect hippocampus and long-term
potentiation.
So, you know, you’ve got this, sort of feed-forward
loop.
But specifically with regards to the, the
master clock, light is what regulates this
master.
[Satchin]: Yeah.
[Rhonda]: It’s what sets it.
[Satchin]: Yeah.
[Rhonda]: So can you…and this was some of
your early findings.
[Satchin]: Yeah.
[Rhonda]: Can you talk a little bit about
that?
[Satchin]: So for a long time people knew
that light resets our clock, and in fact,
in nature, with change of season, the sunrise
and the sunset time do change, and we have
to adapt to that sunrise and sunset time,
otherwise animals cannot go to sleep and wake
up at the right time.
So what is interesting was for a very long
time, people couldn’t figure out what, where
is the light receptor that resets the clock,
because there are many blind people out there
who cannot see anything but they can reset
their clock.
So if they go from east coast to west coast,
they fly, then they also have typical jet
lag and after three to four days they get
used to the new time zone.
And similarly, there are laboratory animals
that are blind, they can’t see a thing, but
if you change their light-dark cycle, then
they readjust in six to seven days.
They actually readjust the same way as mice
with normal vision.
So this was kind of an unanswered question
in vision science for 75 years.
What is this extra light receptor in the eye?
And we knew that it was in the eye because
many people who go to war and lose both of
their eyes because of gunshot wounds, and
people who have cancer or a tumor growth in
both eyes and the eyes are removed, they can’t
reset their clocks.
So they, kind of run free.
They kind of free run, because our clock is
not exactly 24 hours.
And our clock is very close to 24 hours, 24
hours, 15 minutes, 24 and a half hours, something
like that.
So, if we cannot entrain our clock to light-dark
cycle, then every day we’ll be working off
15 minutes or 30 minutes late.
And then after 10 to 15 days, we’ll be completely
out of sync with the society.
And that’s what happens with this [inaudible
00:10:57].
If you combine these two observations, people
without their eyes cannot reset their clock
and blind people can still reset their clock,
then that essentially tells us that there
must some special light receptor.
So almost 16 years ago, three different groups
figured out that there is a new light-sensing
molecule that must be present in some of the
remaining cells of the retina in blind people,
and our group was one among them who discovered
this new light receptor called melanopsin.
It’s actually from frog melanosomes.
So this is a clear example of how basic science
actually leads to understanding human health.
So if you put a frog under light, then the
frog’s skin will change its color.
And because frog skin has a light sensor that
detects light, and then puts kind of a natural
sunscreen.
[Rhonda]: Like melanin making…
[Satchin]: Yeah, and so it spreads melanosomes.
So melanin pigments are spread.
And interestingly, the same protein that spreads
melanosomes in frog skin is also present in
human retina and mouse retina, and only in
1000 to…sorry, 2000 to 5000 cells.
And these are special light-sensitive ganglion
cells, we call them, and these cells sense
light in the blue spectrum and send that information
straight to this suprachiasmatic nucleus or
the master clock.
And that’s how every day, in the morning,
with the first sight of light, these melanopsin
cells sense light and then tell the SCN that
this is morning and this is time to sync up.
So that’s what it is called.
[Rhonda]: Okay.
So that first bright light exposure…
[Satchin]: Yeah.
[Rhonda]: …sets the clock and tells your
body, you know, “Okay, this is the start.”
So then you start to change gene expression,
things are going on in the brain, you’re more
mentally aware of things that happen.
All these little changes happen throughout
the day that are on this rhythm.
[Satchin]: Yeah.
[Rhonda]: What happens, then, if you, let’s
say, you don’t have…let’s say you live in
a very dark apartment or, you know, a dark
apartment in the winter in Sweden or somewhere,
you know, where it’s, like, dark, you know,
so you don’t get that bright light exposure.
How does that affect…
[Satchin]: Yeah.
[Rhonda]: …someone’s circadian clock?
[Satchin]: So you kind of use this interesting
term, bright light.
And actually, that’s very important for melanopsin
because we know we have rhodopsin that’s extremely
sensitive to light and that helps us to see
the star and enjoy the moonlight, but that’s
very low amount of light.
And actually, a clock is not sensitive to
that amount of light.
Just imagine, if our clock was sensitive to
dim light, then we’d be completely what because
even in nature, the lightning or starlight
or moonlight that we can see can reset our
clock.
So, one interesting thing with melanopsin,
it’s very less sensitive to light.
It’s a very lousy photoreceptor.
So that means you need a lot of light.
For example, you may need almost 1000 lux
of light to fully activate melanopsin.
And then another interesting part of melanopsin
is it integrates light over time.
So that means it actually remembers how much
light exposure you previously had.
So for example, if I switch on a flash, then
for 100 milliseconds you see a thing and then
after the flash is gone, your visual system
restart, you don’t see that thing.
But melanopsin stays active for several seconds
after lights are off.
So that characteristic helps you to count
how many minutes you had exposure to light.
So in that way, not only you need bright light,
you also need several minutes of bright light
before it’s fully active and can do all of
its function, particularly to reset the clock
or to do few other functions, and I’ll get
to that.
So, when we discovered melanopsin, we thought
that these cells connect only to the master
clock, but what we’re learning more and more
is it has multiple different functions.
It also connects to part of the brain that
suppresses or that regulates sleep, so that
means many of us know that it’s very hard
to sleep in a lighted room and that’s because
of melanopsin because it senses light, and
in diurnal organisms like us, it does know
there is light, so you’re not sleepy, so you
stay awake.
It also indirectly connects to part of the
brain that produces melatonin, and melatonin
is the sleep hormone.
So, when we have lot of light and also for
a very long period of time, then it shuts
down melatonin.
It helps us stay awake.
But during daytime, in the morning when we
wake up, we need that big jolt of light for
melanopsin to really activate and suppress
the melatonin, make us more alert and reset
the clock, and turn on hundreds of genes in
the SCN and start secretion of many neuropeptides
and all that stuff.
So that’s why it’s becoming…we are learning
a lot about what quality of light and how
much of light do we need in the first half
of the day to keep us awake, and how little
light or what kind of light we need in the
evening or second half of the day so that
we can go to bed well.
So in dim environment, it becomes…means,
many people know that dim light or cloudy
days make us depressed, but now we have a
molecular biology explanation why is that.
At the same time, it also tells us maybe if
we have blue-shifted light during the first
half of the day that may help us to stay awake,
to stay alert, and also to reduce depression.
But in the evening, we actually should stay
away from that light.
So it’s a very interesting thing about our
environment because so far everything in our
environment, whether it’s carbon monoxide,
carbon dioxide, oxygen, temperature, everything
can be set at a set point throughout 24 hours.
And this is interesting stuff about light.
We need more of that in the first half of
the day, and as little as possible in the
last half of the day or in the evening.
So it’s a very interesting area.
[Rhonda]: And modern day society is also not
very conducive to that, those needs because
we have artificial light, we have televisions,
we have computer screens, we have iPhones
and Android phones, and you know, so everything’s
emitting this bright light or blue light…
[Satchin]: Yeah.
`
[Rhonda]:… which is what’s activating the
melanopsin recep-…
[Satchin]: Yeah.
[Rhonda]: …or melanopsin and inhibiting
melatonin production.
I remember reading some study that was published
some years ago where humans that were exposed
to around, I think it was around 10,000 lux
of light, upon, you know, 30 minutes of waking,
so, um…
[Satchin]: Yeah.
[Rhonda]: …you know, early exposure, and
they were exposed to it for a number of hours,
something like seven hours.
I mean, it was, like, bright light, you know,
all day, almost like being outside.
[Satchin]: Yeah, yeah.
[Rhonda]: And then their cortisol levels were
measured at various points in the day.
And so cortisol is one of those hormones that’s
regulated by this, the circadian clock.
[Satchin]: Yeah.
[Rhonda]: And it peaks about the time we wake
up…
[Satchin]: Yeah.
[Rhonda]: …or something like that, right?
[Satchin]: It rises when we wake up.
So that promotes alertness, and melatonin
is the opposite, it [laughs] promotes sleep.
[Rhonda]: Right.
And it also…I mean, cortisol regulates…
in itself, it’s regulating…
[Satchin]: Yeah, huge amount.
[Rhonda]: …you know, 20% of protein-coding
genes.
[Satchin]: Yeah.
[Rhonda]: So it’s doing a lot.
But these people…the thing with cortisol
you want it to peak when it’s supposed to
peak.
[Satchin]: Yeah.
[Rhonda]: And you don’t want it to be active
all the time.
You know, things like chronic stress…
[Satchin]: Yeah.
[Rhonda]: …that can activate cortisol and,
you know, this can lead to dysregulation of,
you know, 20% of the human genome…
[Satchin]: Yeah.
[Rhonda]: …or something like that.
Anyways, these people that were exposed to
the bright light had a 20% or 25% decrease
in cortisol levels, you know, during parts
of the day when it wasn’t supposed to be high.
[Satchin]: Yeah.
[Rhonda]: It’s very interesting how just the
bright light exposure itself…
[Satchin]: Yeah.
[Rhonda]: …seem to regulate the stress hormone
or at least keep it…
[Satchin]: Yeah.
[Rhonda]: …so it wasn’t going out of control.
What about people that, you know, get…so
people that are exposed to bright light in
the evening, so, you know, you’re working
late or you’re, you know, watching television,
and that’s going to trick your brain and think,
“Okay, reset.”
Is that kind of what’s happening?
[Satchin]: Yeah, so what is happening is in
the evening when we have that extended period
of light, it’s sending a wrong signal to the
brain saying this might be part of the day
and that also doesn’t allow melatonin level
to build up so we have trouble going to sleep.
And ultimately, we go to sleep and we wake
up either sleepy or we wake up very late into
the day.
And in the late in the day, then our body
is getting a signal, “Oh, this might be the
morning.”
But at the same time, these days we spend
more than 90% of our time indoors and many
of the indoor environments have less than
1000 lux of light and many places have actually
less than 200 or 100 lux of light.
So that means even though we wake up, we don’t
get that very bright light that we are designed
to get in the morning.
So our body gets confused completely when
it’s day or when it’s night.
Although we kind of can work our way through,
our body is not completely compliant or completely
is figuring out when it’s day or night.
So that’s why all the circadian rhythm, all
these rhythms and gene expression in different
organs are completely desynchronized.
You can imagine a car running with a bad timing
belt and the spark plugs sparking at wrong
time, so you can’t run that car too long.
So that’s what happens in our body.
[Rhonda]: Right.
I know for myself I…there’s a few things,
there’s a couple of things that I, changes
that I’ve made to my lifestyle within the
last year or so that have made a huge difference.
And that is one, I now live in a place that
is not a dungeon.
[Satchin]: Yeah.
[Rhonda]: So I used to have, you know, windows
that were blocked by other buildings and it
was not facing, you know, the west side.
I mean, just no light was coming in.
[Satchin]: Yeah.
[Rhonda]: And that really did affect my mood.
Like, even though I was eating well, exercise,
all these things, you know, that helped, but
I definitely felt that my mood was affected
by that.
So I moved and now have bright light exposure
first thing in the morning which has really
helped my circadian rhythm in addition, so…but
also, I don’t get exposed to bright or blue
light in the evening.
So I have these lights, I don’t know if you’re
familiar with them, they’re Philips Hue.
[Satchin]: Yeah.
[Rhonda]: And so they’re, you can program
these lights to switch off blue light and
only have red light.They do other colors as
well than red light.
[Satchin]: Yeah, yeah.
[Rhonda]: And so I have it now where…well,
now that it’s summertime, I used to have it
programmed with the sunset, but now that the
sun’s setting later, it gets too dark in my
place, so about 5:30 the red lights come on.
[Satchin]: Yeah.
[Rhonda]: And then I have an app on my phone…I’m
sorry on my computer called F.lux…
[Satchin]: Yeah.
[Rhonda]: …which then blocks the, it filters
the blue light…
[Satchin]: Yeah.
[Rhonda]: …and it corresponds to the sunset…
[Satchin]: Yeah.
[Rhonda]: …or the time zone that I’m in…
[Satchin]: Yeah.
[Rhonda]: … or that anyone’s in.
So those are some of the things that I’ve
done, and I now am very much able to go to…you
know, about 10:00 at night, 10 p.m., I’m,
I’m sleepy, I, you know, I brush my teeth,
it’s time for bed, and I wake up now probably
around 7:30, 8:00.
That’s it.
So I get a nice, a good amount of sleep…
[satchin]: Yeah.
[Rhonda] …but it’s pretty regular and routine.
[Satchin]: Yeah.
[Rhonda]: So those are some little lifestyle
changes that I’ve made to my life that have
made a big difference.
What about people, like I’m getting to travel
to Asia at the end of next week, jet lag,
you know, so obviously, when you travel to
another time zone, your circadian clock can
reset.
Do you think the most important thing is bright
light exposure when it’s light?
Is that what’s gonna help reset me?
[Satchin]: Yeah, so it’s a very complicated
question because [laughs] there’s light, and
also there is food, and we’ll get to that.
[Rhonda]: Yes.
[Satchin]: But one important point that you’ve
brought up is jet lag, and although we relate
to jet lag when we travel, there are nearly
15% to 20% of population in this country or
in any industrial country that works in dayshift
and night shift.
So almost in every few days they are going
through that jet lag that we dread to go through.
So for them, it’s very stressful to go from
day shift to swing shift to morning shift
to night shift, and all these shifts.
And what is interesting is most employers
think that it’s very stressful, so let’s let
them do the swing shift or night shift for
maybe four days in a week.
And then for three days, they’re again trying
to be social, they’re trying to catch up with
their friends and families.
So it’s very stressful for them.
And that’s the biggest area where light management
or lifestyle management will have a huge impact
on figuring out how best to schedule this
shift work so that these guys will go from
day to night shift to swing shift without
compromised fitness and with a good family
life.
So we’re still learning how to shift them.
It’s not easy for them to shift in every week
for four days in one shift and three days
in another shift.
But light is a very important aspect of that.
Particularly, individuals who work the night
shift, they come home and they try to sleep
throughout the day in a dark room, of course.
And then, if it is winter time, they barely
get any light, any sunlight or bright light.
And at work, you never get…indoor environment,
we rarely get more than 1000 lux of light.
So these people are continuously staying,
kind of, in a dim winter environment during
that night shift.
And so that’s one area where managing light
will have a huge impact on productivity, health,
social life, etc.
But as I said, light does half of the job,
and then the other half is done by food.
[Rhonda]: Right.
[Satchin]: You also pointed out another thing.
You brought up the example of stress hormone,
cortisol.
Cortisol is regulated by circadian clock,
but at the same time we know it’s a stress
hormone.
So if you have stress in the middle of the
night when cortisol is not supposed to be
high, it will not just wait for the morning
time.
Your cortisol will go up, and we know that.
So similarly the master clock sends the signal
that when it should be day, when we should
be eating, and when we should be fasting,
and accordingly, the liver clock, the gut
clock, all these clocks that time themselves.
And when I say time themselves, what happens
is, just imagine there is, you are kind of
driving in a downtown area with a lot of stoplights
and green lights, right?
And if you imagine if there is no light anywhere,
then there will be a lot of accidents, so
there will be lot of traffic congestion.
So having the lights turned on and off at
the right time help the traffic move.
Similarly, in our liver, if you imagine, we
are eating a lot of different type of food
that has to be metabolized, that has to be
broken down, sorted out, then a lot of things
that we don’t need for our body, for example,
the artificial sweetener, the coloring agent,
the flavoring agent, all of them go to another
conveyor belt.
They get excreted out, and the protein gets
broken down and they build up other part of
the cell.
So a lot of things are going on at that time.
So it’s almost like you are bringing in food,
dividing them into different parts, and moving
through this conveyor belt, the traffic.
So not everything will happen at once.
So there is time for protein to break down,
there is time for glucose to be made, there
is time for nucleotide to be made, there is
time for bile acids to be made, the different
hormones to be made.
So these clocks actually have timed different
things, and when clocks break down, then what
happens is you can imagine there are traffic
jam and a big pile-up.
So the metabolites, metabolism is not efficient
anymore.
There is a lot of byproducts just lying around
and that stresses the cell and then we get
to the disease.
So the point is, although we have clocks,
these clocks also respond to when food is
coming in.
At the same time, when the food is coming
in and the kitchen is not ready, the food
is not going to stay in the garage.
So our body is not built that way.
It will come and then it will light up the
fire and for that we prepare, but then the
traffic lights are not on, so there will be
a traffic jam.
So that’s why the peripheral clocks…actually,
they have a clock but they also respond to
food, and the food tells them when to time
their activity.
So when we travel, our lighting changes and
our food time changes.
[Rhonda]: Yes, yes.
So you kind of are changing gears here and
I think it’s very important to point out for
people that aren’t familiar with this.
So we’ve been talking for some time about
this master regulator clock and the suprachiasmatic
nucleus reaching the brain and how light is
what sets that clock, what regulates that
clock, and in turn, those are regulating a
wide variety of different physiological processes.
[Satchin]: Yeah.
[Rhonda]: But then you just mentioned something
very important, and that is that in addition
to that clock, there are other clocks, for
example, in our liver, in our muscle, in our
hearts that also are regulated, but your research,
and maybe we can start to talk about this,
they seem to be regulated by something different.
[Stachin] Yeah.
[Rhonda] By when you eat, by when you take
in food.
And I know for myself I’ve always…I’ve known,
you know, about the circadian clocks in the
liver and how they regulate metabolism.
I know that, you know, we’re most insulin-sensitive,
you know, during the early morning hours,
and most insulin-insensitive in the evening.
And so I’ve always tried to not eat too late
because, “Well, I don’t wanna eat this high-carbohydrate
meal when I’m the most insulin-insensitive.”
It doesn’t make any sense.
It’s much easier for me to do that in the
winter months when it’s, you know, gets dark
earlier.
I find it more difficult when spring and summer
occur because it’s lighter are out, I’m working
later, you know, and therefore, you know,
I eat later.
But so let’s talk a little bit about how food
regulates…
[Stachin] Yeah.
[Rhonda] …these clocks and these different
tissues.
[Satchin]: Yes.
A few years ago, we started looking at which
genes are regulated by CLOCK in different
organs.
So if we look at liver, there are somewhere
between 3000 to 5000 genes that are turned
on at certain time of the day or night.
And so that’s…
[Rhonda]: A lot of genes.
[Satchin]: A lot of genes.
So, that’s almost 30% of expressed genome
or whatever.
Um, but what is interesting is, we said, “Well…”
We did a very simple experiment where these
are done in mice.
so the night-eating mice…mice usually eat
during the night time, that we asked, “Well,
there is a master regulator in the brain that’s
telling the rest of the body when the timing
is, when it’s day or night, and let’s give
mice food in the middle of the day, just like
the shift workers work in the night time,
they eat.
If we do that, then what happens to the liver?
That all liver genes, that cycle, that take
the cue from light-dark cycle or from the
food?”
Because we have these two groups of mice,
both groups of mice are in the same light-dark
cycle.
One group it’s doing day, one group it’s doing
night.
The liver takes cue from light-dark cycle
then all cycling gene should be identical
in two groups.
If the liver clocks take cue from eating time,
then the day-fed animals will have a different
clock than the night-fed animals.
And that’s exactly what we found, that even
though the light-dark cycle are the same for
both animals, the liver clock responds to
when the mice ate.
So the day-fed animals had the same 3000 genes
cycling.
The night fed animals had the same 3000 genes
cycling.
But now the genes that are turning on during
daytime in the day-fed animals, now they turn
on at nighttime in the night-fed animals.
So that means the time when we eat tells our
liver clock when to turn on the genes and
when to turn off.
The light has very little impact.
We cannot say no impact, very little impact
on the cycling genes in the liver.
So that experiment has been replicated now,
and what we are learning is almost every organ
in our periphery outside the brain kind of
follows when we eat.
So then what becomes very important in the
daily life is the first sight of bright light
and the first bite of food.
Those two determine how our body clocks work.
So now we are working on how this timing of
eating or timing of light affects our health
in general.
[Rhonda]: And you have a certain term, I guess.
I don’t know who coined the phrase, but it’s
called time-restricted feeding.
[Satchin] Yeah.
[Rhonda] And you’ve done…there’s been experiments
that you’ve done in mice where you’ve feed
them various types of food.
[Satchin] Yeah.
[Rhonda] High-fat diet, high-sugar diet, normal
chow diet, and you’ve restricted their time
feeding, you know, during their, the nights,
you know, the mouse day hours, which is actually
the night because they’re nocturnal, and you
found, you know, some very interesting things.
So, can you talk a little bit about those
findings?
[Satchin]: Yeah.
So what we have seen is when we, in experimental
animals, if they don’t have a clock, then
their metabolism goes really weird.
So just like I said, a metabolism works like
this traffic signal in downtown, and if they’re
not timed properly, then there’ll be disease.
Similarly, for very long time we knew in the
field that mice that don’t have circadian
clock because they lack a gene or have a mutation,
they have various metabolic defect.
They have obesity, diabetes, cardiovascular
diseases, etc.
We also know people who do shift work for
a very long period of time, they are also
highly likely to get metabolic disease, cancer,
[inaudible 00:35:27].
So there was this idea that clocks are important.
If we don’t have a good functioning clock,
then that’s bad for us.
Then we went back and asked, “Okay, normal
circumstances, what are the conditions that
can actually break down our clock?”
And what we found was when mice are given
high-fat diet or any unhealthy food, then
the food itself breaks down their clock.
So they actually don’t have a good eating-fasting
rhythm, so the mice eat throughout day and
night.
And we knew that high-fat diet and high-fructose
diet, high-sucrose diet, all of these diets
that are used experimentally in laboratory
condition gave rise to all this disease.
And people always thought it’s what and how
much the mice ate that determined the disease.
But what we found is, well, these mice are
also not eating at the same time.
So maybe when they eat also matters.
We did a very simple experiment where we took
two groups of mice, completely identical set
of mice, no genes were changed, no drugs were
given, and one group of mice ate whenever
they wanted to eat, and we…to begin to with
to give them a high-fat diet.
So they’re getting somewhere between 45% to
60% of their food from fat or calories from
fat.
So that means it will be equivalent to humans
eating all of their food from cheese, nachos,
ice cream, or Western diet.
[Rhonda]: So they’re getting fat and sugar.
[Satchin]: So they’re getting fat and sugar
all this time.
And then other group got the same number of
calories and the same type of food, exactly
identical food, but they had to eat all their
food within 8 to 12 hours in nighttime.
So in some experiments we have done 8 hours,
9 hours, 10 hours, 12 hours, like that, and
the most surprising thing is…and this is
something that everybody, a lot of laboratories
around the world do.
There are 11,000 papers saying high-fat diet
causes obesity.
And we said, “Okay, so now we control for
time.”
So since time was restricted, calorie was
not restricted.
So that’s why we call it time-restricted feeding.
And surprisingly, the mice that ate for 8
to 12 hours, they did not become obese, diabetic,
and they had a normal liver function and they
had normal cholesterol, etc.
And then in the next set of experiments, we
exposed these mice to high-fructose diet,
high-carb diet, high-sucrose diet, all kinds
of diets either ad libitum, whenever they
can eat, or they are to eat within 8 to 12
hours.
And in most cases, we see the time-restricted
feeding has huge beneficial impact.
Even when mice eat standard diet, normal chow,
which is supposed to be healthy, and mice
actually eat most of their food, nearly 70%
of food during night time.
They eat a little bit during daytime, but
if they completely restrict that to 8 to 12
hours, then their muscle mass goes up, their
fat mass decreases, and they are more coordinated.
So if you put them in a rotating drum, than
they coordinate on the rotating drum for a
long time.
So the bottom line is this time, so in these
experiments where we kept what and how much
they ate constant, the only thing that we
changed is when they eat, then we see this
huge beneficial impact, and that correlates
with very robust clock in the liver, and in
other metabolic organs.
And why this is important is two things.
One is many of us have daily bad lifestyle.
I won’t say bad, but we don’t have much control
over what and how much food we eat.
As soon as we get out of our home, all the
food we eat outside we have very little control
over it.
So the only control we have, actually, is
in our time.
So, that’s why we think this can be a good
entry point to a better living by controlling
time.
And then the second thing is it also doesn’t
take away this idea that nutrition doesn’t
matter, that quality doesn’t matter, because
even in our high-fat fed mice, we don’t see
they completely become normal just like the
normal chow-fed mice.
They’re much healthier.
So to have better health, you still have to
change what and how much you eat, but timing
becomes much easier to manage.
[Rhonda]: So you just covered so much.
This experiment that you did right here, this
publication, even before, you know, you’ve
gone onto some small human studies, but this
convinced me to do a time-restricted feeding
schedule because, well, for a couple of reasons,
but…so just, like, to reiterate, these mice
that were fed a high-fat diet, they were fed
the same amount of calories, but those that
ate during their waking hours…
[Satchin]: Yeah, yeah, yeah.
[Rhonda]: …so for mice, which is night within,
I think, it was 12 hours…
[Satchin]: Yeah.
[Rhonda]; …they gained…I’m sorry, they
had 70% less fat mass.
[Satchin]: Yeah.
So they had 28% less body mass total.
[Rhonda]: Right.
[Satchin]: And that change in body mass is
mostly due to fat because they had 70% less
fat.
[Rhonda]: That’s amazing.
[Satchin]: Yeah, that’s really…
[Rhonda]: Right there and they’re eating the
same crappy food, but they’re eating it when
their liver can process it the best, you know,
when they’re, you know, able to regulate their
blood sugar, when they’re able to oxidize
fats, things like that.
So, that was really cool.
And then the second thing was, you know, I
eat very, very, very health-conscientious.
I try to get a wide variety of vegetables
and fruits, and good fats, and, you know…
[Satchin]: Yeah.
[Rhonda]: So all that stuff, omega-3s but
I’m always trying to find more…the low hanging
fruit to sort of delay the aging process in
a way, or become, you know, as optimal as
I possibly can.
So, the mice that were fed a normal chow diet,
you know, high in fiber and all these things,
vitamins, you said they actually had more
lean muscle mass.
[Satchin]: Yeah.
[Rhonda]: That is very interesting because
for me, it’s much easier to lose fat than
it is to gain muscle.
It’s difficult to gain muscle and as you age,
it becomes even more so.
[Satchin] Yeah, yeah.
[Rhonda]: And muscle mass is very important.
It protects you from frailty, things like
that.
So, any ideas as to how just restricting your…we
should probably talk about what starts that
clock.
[Satchin]: Yeah.
[Rhonda]: What food is it?
You know, it doesn’t necessarily have to be
a calorie, right?
It can be black coffee or something like that.
But anyways, any ideas as to what, you know,
is allowing you to keep on more muscle mass?
[Satchin]: Yes, so that actually is a big
mystery, because in the first series of experiments,
we are essentially reporting observations.
What happens.
The reason why we looked into muscle mass
is initially we thought that these mice, when
they’re going through such a prolonged period
of fasting, in some experiments they are going
for 12 to 16 hours of fasting every day.
And many would think that when you go through
this prolonged fasting you would lose your
muscle, because muscle, the protein gets used
to make glucose.
That’s why you measure lean mass.
And surprisingly, we found that the lean mass
actually increased, whereas their fat mass
decreased.
That was a big surprise.
That’s what we reported, but we haven’t looked
at exactly why the muscle mass increases.
But what we are seeing recently is there is
some correlation.
Other people have published recently that
nicotinamide riboside, this is a precursor
for NAD, if that is given to mice, they also
gain muscle mass or they maintain their muscle
mass, and this nicotinamide riboside is converted
to energy, and increased amount of energy
is always better for any cell because that
is the precursor to the energy currency of
the cell, that’s ATP.
And what we are seeing is in many of our mouse
experiment, we see the energy level actually
goes up slightly.
So this is a natural way to boost up energy
level, not only in muscle, in almost every
organ.
So I think that might be one of the many different
reasons why we’re gaining muscle mass, but
we can’t explain with the current data why
they gain muscle mass.
[Rhonda]: Okay.
Can I ask you another question?
[Satchin]: Yeah.
[Rhonda]: So I do know that there are some
genes, by the way, that are involved in nitrogen
balance that are regulated by circadian rhythm,
but that’s…
So I also remember in your paper, I don’t
know if it was the same paper or different
one, I think it was the same paper, but you
also found something very interesting, and
it’s kind of along the same lines here and
I’ll tell you where I’m getting at.
But you also found that animals that were
fed during a nine-hour period had improved
endurance.
[Satchin]: Yeah.
[Rhonda]: Not improved muscle strength, but
improved endurance, and to me, when I read
this, I thought, “Oh, well, if you think about
endurance, endurance is aerobic.
It requires aerobic respiration, which means
it requires oxygen, which means it requires
mitochondria because mitochondria are what
make energy in the presence of oxygen.”
So have you thought about looking…and this
kind of goes along with your NAD hypothesis,
but had you looked at mitochondrial biogenesis,
mitochondrial function?
`
[Satchin]: Yeah, so the endurance is a very
interesting aspect because we see that only
when mice eat for eight to nine hours.
We don’t see that improved endurance when
they eat for 12 hours, although their body
weight is maintained as nine hours.
So this was interesting.
So that’s why, as you pointed out, clearly
mitochondria might be playing a role, and
in fact, in liver we do see increase mitochondria
volume, and increase endoplasmic reticulum
volume, so ER and mitochondria kind of work
together.
That’s what we are learning these days.
So the mitochondria volume increases.
Another thing is we do see less damaged mitochondria
in liver when they eat only from eight to
nine hours.
Second thing is this mitochondrial effect
is not restricted only to liver.
We do see increased mitochondrial volume in
brown adipose tissue, so in brown fat.
As you know, these mitochondria have kind
of dissipate until they are literally burning
the fat.
So, at least in two different organs, we have
seen increased mitochondrial volume.
That correlates with increased level of PGC-1alpha
that’s involved in mitochondria biogenesis.
So, there is all these links that we are seeing
and that are also giving us clue where to
look for the mechanism.
For example, why PGC-1 level goes up and what
triggers that to go up.
[Rhonda]: Well, this actually leads me into
another area that I wanted to cover.
So before we go into the flies and humans,
and that is I think people may be confused
by this time-restricted feeding, which is
essentially, you know, feeding within our
active hours.
[Sachin] Yeah.
[Rhonda]: The daylight hours, and intermittent
fasting.
So there’s obviously some overlap between
the two because if you’re, let’s say, you’re
feeding within a 12-hour period.
So you wake up, you have your first sip of
coffee, that starts your clock.
All right.
That’s it.
So, 8:00, then you better stop eating by 8
p.m.
Right?
That’s for 12 hours.
[Satchin]: Yeah, yeah.
[Rhonda]: Then from 8 p.m. all the way till
8 a.m. the next morning, you’re fasting, right?
[Satchin]: Yeah, yeah.
[Rhonda]: You’re not getting any energy.
[Satchin]: Yeah.
[Rhonda]: So, so in some ways you’re getting
a lot of…there are some overlap between
this time-restricted feeding and intermittent
fasting, for example, which has been shown
to increase ketone bodies like beta-hydroxybutarate,
which I know you’ve also shown restricted
feeding does increase that as well.
It takes around, I think, 10 to 12 hours…
[Satchin]: Yeah.
[Rhonda]: …for your liver glycogen to deplete
and fatty acids get immobilized, they go to
the liver, you start to make beta-hydroxybutyrate
and other ketone bodies which then get transported
to other tissues and are used for energy in
the brain, or they act as signaling molecules.
[Satchin]: Yeah.
[Rhonda]: Which Eric Verdin at UCSF published.
There’s lots of…oh, have…can you, first
of all, differentiate for people, like, the
difference between intermittent fasting and
time-restricted feeding?
Like, what are the main differences, and maybe
what some of the similarities are?
[Satchin]: Well, both of these depend on this
idea, as the commonality is this prolonged
period of fasting.
When I say prolonged, that’s usually longer
than six to eight hours because that’s how
long it takes for glycogen to deplete or maybe
the fatty oxidation to begin so that we begin
to use some of the fat.
And you also pointed out ketone bodies and
beta-hydroxybutyrate, those are also produced
maybe after 8 to 10 hours.
So the bottom line is this, that is when we
eat we have a type of physiology where we’re
using glucose and we’re driving some bodily
function.
And at the same time, we may be also damaging
some cellular components because of all the
reactive oxygen species that we generate during
eating, during metabolizing all of this.
So all of these have to be repaired, and for
some reason, we do not know why, the repair
mechanism happens only during the period of
fasting.
And during this period of fasting, we switch
to a different kind of metabolism.
Just like you said, our primary energy source
is not the readily available glucose from
food anymore.
It has to come from different sources.
In some cases it can come from a little bit
of protein, that’s gluconeogenesis or from
fat oxidation or, just like you said, ketone
bodies.
So these things, this physiology, the fasting
physiology, we actually know…we are just
seeing the tip of the iceberg of fasting physiology.
We’re just learning about a very few molecules.
We don’t know what happens to lot of signaling
molecules, how the mitochondria actually repair
during fasting.
Is it actually necessary, to why some repairs
happen only during fasting.
Why can’t they happen when we’re eating?
So all of these questions are out there but
what is common between this intermittent fasting
and time-restricted feeding is this fasting
physiology that we’re beginning to understand.
The reason why we coined and use the word
time-restricted feeding is we are not restricting
calories, at least in experimental animals.
So in that way the intermittent fasting came
from calorie restriction, and every other
day feeding that had a serious component of
caloric restriction that many people thought
is difficult to achieve.
So that’s why we stayed away from the word
caloric restriction or fasting, and we used
the word feeding because people thought, people
may have a positive attitude towards it.
Other than that, I think the idea of fasting
is ingrained in evolution.
Just like in circadian rhythm, the animals
have access to food only during their awake
time which can be less than 12 hours, and
also for diurnal animals, which are hunter-gatherers,
the only time, actually, they have to hunt
is twilight time because if you ever go to
Savannah, or any of the African countries
where there is still wild animals, or if you
go to even a zoo, then you know that animals
are not active in the middle of the day.
They’re mostly active during morning and evening.
So in nature, animals actually have only two
chances to eat, and the rest of the time they’re
fasting.
So this fasting physiology is a very natural
response to repair and rejuvenate, and in
time-restricted feeding, we’re kind of exploiting,
or we’re kind of bringing back that primordial
physiology that’s ingrained in our genome,
that our genome has to respond to that fasting
on a daily basis.
At the same time it syncs with another aspect
of the genome; that is it helps us stay awake
for 10 to 12 hours and to reduce our energy
level and go into a sleep or less active state
for the rest of the day.
So in that way, it brings back the primordial
rhythms in our physiology, metabolism, repair
and rejuvenation, whereas intermittent fasting
actually helped us to learn various basis
for this fasting physiology.
[Rhonda]: That makes sense.
I guess, also, what I was wondering is if
you think about it, like, so the minute you
start your metabolism clocks in your liver,
for example…
[Satchin]: Yeah.
[Rhonda]: …the minute you start those metabolism
clocks by your first sip of coffee and breakfast,
the clock’s ticking and you’re insulin-sensitive.
You’re gonna be able to, you know, take glucose
up into various cells after you eat.
And then once you get past that time, so you’re
now 12 hours out, you’re not gonna be as insulin-sensitive.
So, let’s take someone that is doing intermittent
fasting, and they wake up at 6:00 or 7 a.m.
They have coffee and breakfast, a big breakfast,
and they’re done.
So then they fast for 12 hours, so now it’s
7 p.m., maybe 13 hours, 7:30, 8 p.m.
They’ve been fasting all day, so they’re getting
a lot of the activation of some of these…
[Satchin]: Yeah.
[Rhonda]: …you know, stress-response pathways
like AMP kinase and, you know, they’re making
some ketone bodies, Kreb, all these similar
pathways are being activated.
[Satchin]: Yeah.
[Rhonda]: …that, you know, time-restricting
feeding also activates.
But then, they take a big meal at 7:30 or
8 p.m., so 12 or 13 hours after they’ve already
set their clock.
[Satchin]: Yeah.
[Rhonda]: So now in theory, then, they’re…well,
I don’t know if this is true or not, maybe
the intermittent fasting changes some of this,
but, you know, their liver wouldn’t be, you
know, it wouldn’t be working as well at that
point.
Or do you think that just because they were
fasting all day that may change some of that
and allow them to then eat this meal and it
wouldn’t have such a negative effect?
[Satchin]: Yes, so that’s a very interesting
question that we get many times and we are
thinking of addressing that.
It’s very hard to do that in experimental
animal models because if you fast them, if
you give them two meals, they reduce their
caloric intake, but it’s possible to do.
But here is something that came out only in
last three to four weeks.
You mentioned early in our conversation that
insulin sensitivity is not the same at the
end of the day, and the question is, if you
fast enough during the day, is your insulin
sensitivity as good enough as in the morning?
[Rhonda]: Right.
[Stachin]: Then everything you can equalize
is at least insulin, which is a big thing
in metabolism [inaudible 00:55:42].
So recently, what we are finding is actually
the smoking gun came almost 10 years ago when
people who are doing GWAS studies to find
whether there are mutations in given genes
that make us more diabetic or obese, surprisingly,
people thought that, “Okay, so we’ll find
some genes that regulate metabolism.”
Right?
So that is the common sense.
But then the big surprise was they found melatonin
receptor as one of their top hits.
[Rhonda]: Wow.
[Satchin]: And some of the clock genes, like
cryptochromes, in the top five or ten genes.
That is not only in one study.
In multiple studies, they found it.
So there are the smoking gun.
What is melatonin doing with this obesity
and diabetes?
And recently, what is interesting is people
are finding that melatonin receptor is present
in pancreatic islet cells, beta cells, and
melatonin receptors, when it’s engaged with
melatonin, it signals and it inhibits insulin
secretion.
[Rhonda]: What?
Really?
[Satchin]: Yeah.
So it just came out, like, four, five weeks…
[Rhonda]: Wait, so you know that I’ve always
wondered, because, like, most of the melatonin
in the body is actually made in the gut, right?
So tryptophan from dietary protein gets converted
into serotonin…
[Satchin]: Serotonin.
[Rhonda]: …and that’s converted in melatonin.
This is happening in the gut and…
[Satchin]: No, serotonin goes to pineal and
then gets into…
[Rhonda]: So there’s, so this, so the, it
happens in the gut and it also happens in
the brain?
[Satchin]: Yeah.
[Rhonda]: There’s two separate genes that
do this.
[Satchin]: Yeah.
[Rhonda]: And what’s really interesting is
I don’t know what melatonin…why are we making
it in our gut?
So I’m wondering if it’s somehow signaling
to the pancreas.
[Satchin]: Yeah, so this is completely new.
So that’s why now it brings up…now, it helps
us to connect this dot that people have.
I mean, for the last 35 years clinicians know
that the insulin sensitivity is very different
between day and night.
And then the GWAS, the human genetics people
came and said, “Yes, there is some smoking
gun with melatonin.”
And now, finally we are finally saying, “Yes,
melatonin receptor can actually inhibit insulin
secretion.”
So in that way, having an evening meal, maybe
with candle light dinner, is not a good idea
because you have less light, so you have more
melatonin, and that can inhibit… [laughs]
[Rhonda]: That’s fascinating.
I have to get that study.
It’s very, very interesting.
[Satchin]: So that’s one case where we might
think that late night, even if you control
food calorie, the same calorie taken in late
in the night versus early in the evening might
have different effect.
In fact, there was one study that came out
from Spain, two or three years ago now, showing
that in a weight loss trial they actually
found…although everybody got the same diet,
they were controlled for activity, clearly
there were two groups of people.
One group lost weight significantly, a lot
of weight loss, and the other group lost moderate
amount of weight.
And when they did post-hoc analysis to see
what is the difference, the only difference
they found was the group that lost weight,
they actually had their lunch…in Spain,
people eat lunch at 3:00.
So they ate lunch earlier whereas the group
that did not lose weight, two months, they
ate their lunch later.
So that is another piece in the puzzle saying
that late-night eating might actually prevent
weight loss.
[Rhonda]: Right.
And you’ve now translated some of these findings
into some human trials using this smartphone
app that you’ve developed.
So that’s kind of neat as well.
[Satchin]: Yeah.
So one thing was we wanted to see is when
people actually eat.
And in typical nutrition studies, people are
asked, “When do you eat lunch, breakfast,
and dinner?”
But that doesn’t capture, really, all snacking
and everything.
So that’s why we thought how to capture when
people eat in a very evidence-based manner.
And we thought if we asked people to take
a picture of their food, then the picture
will speak a volume.
It will have every single component.
They would not have time to describe everything
on their plate, but we’ll capture that.
It will also have the timestamp.
So the whole idea was to see when do actually
people eat.
Are there a lot of people who eat like mice
do that nibble throughout the day and night?
And if they actually eat until, say for more
than 12 hours or 13 hours, then they are the
ones who may benefit from time-restricted
feeding.
So when we did this experiment, when we started
this project, we thought that…everybody
we asked, they would say, “Yeah, I wake up,
I have my first sip of coffee and usually
I eat all of my food within 12 hours.”
So we were very discouraged to hear that.
But then we carefully selected people who
don’t do a shift work so they will not have
to work in the nighttime, that’s when they’re
changing their eating time, and they’re also
not on any medication that will change their
hunger or satiety.
So we took really healthy people from San
Diego area because we live here, and they
just had to take a picture of their food.
And that way, it was also less stressful for
them to enter what they ate, and portion size,
etc.
[Rhonda]: Way better compliance, I’m sure.
[Satchin]: Yeah.
There’s only three clicks, because if you
think about it, open the app, take a picture,
and then press the save button.
And the optional was they could actually describe
what they ate.
But we found very few people actually describe
what they eat.
So that means just typing that on your left
hand when you’re eating is not a very pleasant
experience.
What we found is out of these 156 people,
nearly 50% people eat during 15 hours.
So that means between their first bite, non-water
bite, to the last non-water bite or sip in
a given day is around 15 hours, which some
people think, “Oh, that’s normal because if
they start their first sip of coffee at 6:00
in the morning, and then after dinner they’re
watching their favorite show, and then had
another glass of wine or chips, that can go
up to 9 p.m.”
But then we asked…well, in mice, we can
actually take away food and enforce time-restricted
feeding.
We can’t do that with humans.
They have to be self-motivated.
So we asked whether it’s feasible for some
people to at least restrict the time.
So we asked eight of them to see…they were
eating for 14 hours or longer and they were
a little bit overweight, so we asked if they
can eat within 10 to 11 hours.
And we said, “We are not going to ask you
to change what and how much you eat.
The only thing you have to do is select your
own time, depending on what time you go to
work or what time you come back, select your
own time until we’ll have 10 to 11 hours and
try to stick to it every day, even on the
weekend.”
And surprisingly, all of these eight people,
they self-selected their 10 hours, 10 to 11
hours, and they stuck to it for 16 weeks,
and at the end of 16 weeks they came back.
We saw that they had lost around 4%, 3.8%
body weight within the 16 weeks.
They didn’t have to do too many, they didn’t
have to read labels, they didn’t have to type
portion size.
But then when we asked them, “Why did you
do it,” what is surprising is they said they
slept better and they felt more energetic
in the morning, and that’s why they did it.
And since they didn’t have to count calories,
it was also good.
But what is surprising is in mice, if you
do the same experiment, mice will chow down.
They will eat the same number of calories
as when they have free access to food.
But in humans, these people in our study,
they actually ate 20% less calories.
Even though we asked them to reduce their
time, they ultimately reduced their calorie.
But if you think about it, this is a much
better way to control, manage their diet than
to count calories.
So in some way this study is inconclusive
to say whether time restriction alone was
beneficial for weight loss.
But what it showed is the feasibility that
some people can time-restrict and that can
be an indirect way to reduce your calorie.
And since we’re collecting picture of every
single food, we can also ask another very
simple question.
“What is the time of the day when people are
more likely to eat certain type of food?”
As you can imagine, we found people drink
most of their coffees, 70% of their coffee,
within four to five hour’s interval in the
morning.
And people ate 70% of their alcohol in the
evening, four to five hours.
So now imagine if somebody’s time restricting
to the daytime, then he or she is more likely
to lose on alcohol.
So in that way, that also improves the quality
of diet.
So since we humans eat different type of food
at different time of the day, depending on
which interval we choose may indirectly result
in change in nutrition quality, and to some
extent, quantity.
[Rhonda]: And what about the cutting out,
like, the ice cream and desserts?
[Satchin]: Yeah, so most of the reduction
in calorie was due to reduction in late night
snacks.
[Rhonda]: Yeah.
[Satchin]: And after dinner, ice cream, dessert,
and alcohol.
[Rhonda]: So this is a really cool idea, Satchin.
I went to your website last night, mycircadianclock.org.
Very, I really like the website in general.
There’s a blog section, the section explaining,
you know, a lot of the science behind circadian
clocks and everything that we’ve talked about
today.
There’s some presentations of you there.
I mean, it’s just a really great website.
But I also signed up for the app.
[Satchin]: Yeah.
[Rhonda]: Because I am now on a time-restricted,
you know, feeding schedule.
And, you know, right now I’m doing 12 hours.
I would like to try the nine hours to see
if I can get any endurance benefits, which
may possibly be mediated by beta-hydroxybutyrate

[Satchin]: Yeah, yeah, yeah.
[Rhonda]: …because that’s been shown to
affect endurance.
But anyways, so I went up and I signed up.
It’s really simple.
You go to the website, you click…maybe you
want to explain.
Like, I clicked Sign Up or something and then…
[Satchin]: Yeah, and then it asks you very
simple questions.
So the whole idea was if you think about it,
this branch of science, circadian rhythm or
circadian research, came out of curiosity.
So we actually don’t have a traditional medical
school department which will take our results
and translate to public.
Or it’s not even in the public health curriculum
because circadian rhythm is such a new field.
That’s not there.
So, it’s hard to…
[Rhonda]: This is so important, and it’s,
like, disrupted by modern day society.
I mean, it’s, like, I’m gonna be talking about
this now.
So I’m very excited.
This is definitely important.
[Satchin]: No, what I was saying is that if
you…you brought up this modern day society.
In modern day society, light is an enabler.
[Rhonda]: You work?
[Satchin]: Light enables us to stay awake
throughout the night, and then we have 15%
of work force who does night shift work, and
they are the ones who actually enable the
rest of us to stay awake.
They are the ones who are actually driving
the truck, who work in the emergency department,
they are food prepping, they are doing all
these other service jobs, and they enable
the rest of us to stay awake.
And then in their way, within the last 100
years we have gone tremendously from a very
natural day and night cycle to 24 hours light
cycle, and that’s the biggest disruption we
see.
And that biggest disruption leads to all types
of chronic diseases that we see in modern
days.
For example, now, out of the top 10 causes
of death, if you look at the top 10 causes
of death in industrialized country, the five
or six, top five or six are chronic diseases,
and we know circadian disruption can lead
to those chronic diseases.
So now the question is if we can do very simple
adjustment to our lifestyle, can we prevent
this chronic disease by X number of years?
So to get to that we need two different information.
One is what are the extent of circadian disruption?
When do people go to sleep?
When do they get up?
When are they eating their food?
And when are they exercising?
So if we can capture what, when, and how much
people eat, sleep, and move around, then we
have a very complete, nearly complete picture
of somebody’s lifestyle that will be highly
useful for circadian rhythm research, for
your primary care physicians, and also for
public health and epidemiology.
So that’s the first part of the goal, to collect
what, when, and how much people eat, sleep,
and move around on a daily basis, for at least
a week or two weeks so we’ll know how is their
lifestyle during weekday and weekend.
And then in the second phase, we can give
some health information, because many of the
health clubs are more geared towards losing
weight, doing one thing, and it’s very difficult
to really guide people to do this three different
things; eat, sleep, and move around on a timely
basis.
And it’s a challenge.
We are experimenting.
So we are actually hoping that some people
who are signing up, they will give us feedback
how to improve our science and also our education
and our app so that we’ll see the benefit.
In the second phase, they can self-select,
just like you said.
You’re going to self-select 12 hours, maybe
9 hours.
And when you self-select an interval and enter
all of your food, and sometimes even if you
forget once in a while, that’s okay, because
we account for that.
We knew we have some algorithm.
And then we want to correlate whether this
9 hours is beneficial to you or not, or whether
some people actually get the same benefit
with 12 hours.
Some people might go to 8 hours or 9 hours.
So those information will come in the second
phase that goes from second week ’til 16 weeks.
Then if you want to continue, we have many
users who want to continue for a year or two
and they want to see how seasonally their
eating pattern, sleeping pattern changes,
that they can have the data and also we gain
from that data, research gains by taking that
data and seeing what is the pattern in the
general public.
[Rhonda]: Yeah.
Also, it’s nice to feel like you’re contributing
to research, you know.
[Satchin]: Yeah.
[Rhonda]: So in addition to this, this myCircadianClock
app which is on the AppStore.
[Satchin]: And also in Android.
[Rhonda]: Android.
[Satchin]: Yeah.
[Rhonda]: And in addition to that app, you
can sync with other fitness data like MyFitnessPal,
because you’re gonna be measuring at all these
other health parameters.
[Satchin]: Yeah.
[Rhonda]: I heard you mention something also
about a light sensor thing or some…
[Satchin]: Yeah, so I wear a light sensor.
[Rhonda]: Yeah.
[Satchin]: It senses light.
But let’s go back to the HealthKit and Google
Fit.
So most phones now have…if it is a iPhone
it has something called HealthKit that comes
with your operating systems, so it’s already
in your phone.
[Rhonda]: Mm, that’s good.
[Satchin]: And that phone, that HealthKit
app is sensing every time your phone moves.
So it’s almost like it’s measuring your movement
just like the Fitbit does and it stores that
data.
It also stores many other kind of data, if
you want to store.
For example, your own information about your
body, your height, weight, age, etc.
And it can record up to, I think, 70 plus
different parameters depending on if you are
using a special app or even the same app,
if you say what do you [01:12:13] for other
companies and it can store that.
But what is interesting is that information
is not on the Cloud, so it always stays on
your phone.
If you lose your phone, you lose that data.
But what you can do is if you want to share
what is in your HealthKit or Google Fit…Google
Fit is very similar to HealthKit, but it runs
on Android…what you can do is you can sync
that data with an app like myCircadianClock.
So anything, any information that you store
in HealthKit gets shared with myCircadianClock,
and myCircadianClock can also send some data
back to HealthKit.
So it kind of acts as a hub.
So similarly, various apps like MyFitnessPal,
and then Nom, and many diet apps, many exercise
apps, they also deposit their data to myHealthKit,
sorry, HealthKit or Google Fit.
So it’s kind of a data exchange hub.
So if anybody has any app where they are measuring
what, when, and how much they eat, sleep,
and move, or any blood parameter, any other
health parameter they are interested in sharing
with researchers, they can sync that to HealthKit
and then HealthKit gets synced with myCircadianClock
and we can capture all that data and we’ll
analyze.
[Rhonda]: Very cool idea.
I am looking forward to contributing…
[Satchin]: Yeah.
[Rhonda]: …to that.
But I kinda, wanted to…
[Satchin]: Talk about the light?
[Rhonda]: I wanna talk a little bit about
your…so you’ve got so many awesome…so
much awesome research coming out of your lab.
There’s also the heart rate…
[Satchin]: Yeah.
[Rhonda]: Heart rhythm….
[Satchin]: Yes.
[Rhonda]: …studies.
So you mentioned earlier the chronic diseases.
If you look at in the United States or industrialized
societies in general, the number one killer,
people died in most of heart disease.
[Satchin]: Yeah.
[Rhonda]: Some sort of heart disease, you
know, and obviously, lots of different things
regulate our susceptibility to heart disease.
Metabolism, obesity.
But you found some very interesting findings
doing time-restricted feeding in fruit flies.
[Satchin]: Yeah.
[Rhonda]: So can you talk a little bit about
that?
I’m very interested in that.
[Satchin]: Yeah.
So fruit flies are used in science for many,
many years.
And they’re, they have a short lifespan.
They stay alive maybe 9 to 10 weeks max.
So it helps us to figure out whether any intervention,
like time-restricted feeding, will have any
positive or negative impact on health span
or healthy lifespan or longevity, etc.
So what we did was, again, a very simple experiment.
We took fruit flies and we gave them food
only for 12 hours during daytime, because
fruit flies are diurnal animals, they fly
around during daytime, eat, and then at nighttime
they sleep, or they had access to food for
24 hours, and we measured that they were eating
the same amount of calories, and they were
also moving around the same distance.
So, inside these bottles they could fly back
and forth.
And at three weeks of age, their heart is
very healthy.
It beats rhythmically.
And although the fly heart is not like human
heart, they also have…
[Rhonda]: Most people are probably shocked.
Flies have a heart.
[Satchin]: Yeah.
So their heart is very similar genetic program.
In fact, many of the genes that are now known
to be necessary for heart development in human
were discovered in flies and vice-versa.
There are many diseases in humans.
Those are now put into flies to see what do
they do in the heart.
So it was a very interesting model.
Just like humans, the fly heart also becomes
weaker with age.
So, by five weeks, the hearts don’t beat rhythmically.
They have a little bit of arrhythmia, and
then they have the same dialysis.
And so then the heart gets dilated with age.
The beat-to-beat distance also becomes very
irregular.
So what we found was when these flies eat
only for 12 hours, they don’t develop that
arrhythmia as quickly as the normal flies
do, so they are protected from this heart
disease.
Then we said, “Okay, so if we introduce time-restricted
feeding later in the lifespan, then what happens?”
Because one thing we could not do in mouse
study, because mice live for three to four
years, we could not introduce time-restricted
feeding later in life.
But in flies, when we introduce later in life,
they were also protected.
The arrhythmia reduced in flies.
And when we gave high-fat diet to flies, they
also produced arrhythmia and many heart conditions
that we see in humans and those were also
protected in flies.
And what is interesting in flies, we also
saw the flies sleep better when they eat only
for 12 hours.
So by five weeks, flies actually are just
like very old people.
They have fragmented sleep at nighttime, and
they are sleepy during daytime, and that is
completely prevented by time-restricted feeding.
They have a good night sleep, they are very
active during daytime, the heart pumps nicely.
[Rhonda]: Wow.
Did you measure heart rate variability?
[Satchin]: Yeah, so we did heart rate variability.
So there are seven different parameters we
measured.
[Rhonda]: And that improved?
[Satchin]: Yeah, so all those seven parameters
improved to some extent.
And when we introduced later in life, they
also improved.
That was the surprise.
[Rhonda]: Do know what or why?
What’s…
[Satchin]: Yeah, so what we found is, again,
one connection was back to mitochondria.
What we found was the mitochondria were healthy,
or in the sense, they did not…they may not,
maybe they were not producing as much of the
reactive oxygen species.
[Rhonda]: The mitochondria in the cardiomyocyte,
in the heart cells?
[Satchin]: Yeah, in the heart cells.
[Rhonda]: Okay.
[Satchin]: So we took the heart cells and
did gene expression for flies.
We looked at all the genes, what we found
is a big cluster of genes whose expression
actually reduced.
And those are from the electron transport
chain.
So that implied that maybe they have less
reactive oxygen species, or maybe reduced
activity of ETC, electron transport chain,
is beneficial.
So then to prove that, we actually knocked
down few components of ETC and those flies
also have better heart.
So that was one thing.
[Rhonda]: Interesting.
[Satchin]: Second thing that we found is proteostasis
of protein folding is necessary and in many
other organisms people have shown that in
different components of protein folding machinery.
But here, what we found is there is a new
protein folding, a very newly-identified folding
machinery called ATP-dependent.
It’s a chaperonin complex.
Eight different components form this barrel-like
structure to fold proteins.
And this requires energy, and that CCT component
has been shown to be important for various
muscle, sorry, various cytoskeletal protein
folding, and it make sense for heart.
And in fact, in humans there is a point mutation
in one of these ATP, sorry, CCT component
that has been shown to predispose to some
heart disease.
So it’s a beautiful story where found both
mitochondria and this protein folding machinery
are necessary for this time-restricted feeding
beneficial, if beneficial effect.
[Rhonda]: And this time-restricted feeding
was 12 hours?
[Satchin]: No, it’s 12 hours because flies
are different from us.
They don’t have thermoregulations, so when
they fast for a longer time, they cannot,
they kind of can’t tolerate that.
[Rhonda]: Oh yeah, they’ll, they’ll get cold.
Okay, so, you know, some of these phones also
measure heart rate variability.
[Satchin]: Yeah, so it will be interesting.
[Rhonda]: That would be interesting, very
interesting because that’s like, you know,
that’s something that supposed to be very
important for having a healthy heart.
But if you don’t mind…again, this is just,
it’s another reason why this time-restricted
feeding, it just seems like everyone should
be doing it.
It’s an easy lifestyle adjustment.
I mean, easy enough.
You have to be disciplined to some degree,
but, you know, it’s not…it’s easy enough
that you can do.
It’s like, you know, by the time it’s 12 hours
later, all right, that’s it, you got to make
sure you get all your food, your whatever
it is that you consume within that 12-hour
span.
But something…I wanna shift gears, if you
don’t mind.
[Satchin]: Yeah, sure.
[Rhonda]: Another organ, the gut, because
it’s another area of interest of mine, and
you recently published that the gut microbiome,
so we’ll quickly go through this.
The gut microbiome is also…well, bacteria
are living organisms and they are also on
a circadian rhythm.
And what I found very interesting from some
of your recent work is that you showed that
different bacterial species within the gut,
at least in a mouse also seemed to, you seemed
to have more of these species during certain
times of the day and less during certain times
of the day.
And this was different in obese animals versus,
you know, non-obese animals or…
That is very fascinating.
Can you explain that just…
[Satchin]: Yeah, so bacteria, they’re just
like us.
They need their own niche, they need their
own pH, temperature, nutrition, and all these
factors.
And now we can imagine that when we eat, we
kind of change the gut environment, the content
of the gut slightly so that some bacteria
may find it easier to grow and then some other
bacteria may find it very difficult to grow
in that condition.
So what happens is when we eat in a time-restricted
fashion, we have a very fixed eating and fasting
interval.
Then during eating, that environment will
promote a certain set of bacteria to bloom
and then the other bacteria kind of become
quiescent, quiet.
And then after few hours of fasting, then
the second set of bacteria will bloom.
So in that way, what it helps is, it helps
to nurture different, a wide variety of species
to cohabit in our gut.
And they also function at different time of
the day.
During the daytime so, for example, when we
are eating we need lot of bacteria to break
down starch and fibers, complex carbohydrates,
and also conjugate some bile acids and etc.
So we need different players to do different
things throughout day and night.
And by time-restrict feeding, this alternating
two different types of environment, one where
there is lot of food and the pH is very different,
versus one when there is fasting, there is
scarcity of food, and the pH is very different,
by alternating between these two different
environment, we promote this diversity inside
the gut.
And why this is important is we actually don’t
understand why, but research from a very different
field, from gut microbiome field, they are
now finding it’s much better to have a more
diverse microbiome in your gut than to have
only one or two very simple species.
So in some way, by having the time-restricted
feeding, it promotes the diversity
There are few interesting thing that we found,
which we are still working on to figure out
why it happens, for example, mice that are
time-restricted feeding, although the bacteria
could break down the complex carbohydrate
to simple carbohydrate, for some reason that
simple carbohydrate could not be taken up
by the gut.
It actually went out in the poop.
And that was a surprise because usually simple
carbohydrates are the ones that get absorbed.
So we think that this compositional change
somehow protects the complex carbohydrate
in the upper intestine.
So it comes back to the lower intestine where
it gets degraded, but we know that the lower
intestine doesn’t absorb sugar.
It’s all in the upper intestine.
So in that way, by this compositional change,
we can completely shift how nutrition is even
absorbed into the gut.
The other thing that we also found is bile
acids, which are very…emerging as very important
players in health, those bile acids are also
better managed with time-restricted feeding,
both in the liver and also in the gut.
Bile acids are made in liver and then they
cycle back and forth between gut and liver.
And bile acids are made from cholesterol.
So there is an enzyme in liver that gets upregulated
in time-restricted feeding.
And that enzyme breaks down cholesterol to
bile.
So you get dual benefit.
You reduce cholesterol, increase bile acid.
And that bile acid comes to the gut and it
helps absorb some fat back into the gut and
there it gets conjugated by this bacteria.
And for some reason we don’t understand, in
time-restricted feeding they get modified
in a different way than in normal feeding.
So these are some of the new research directions
we are taking or trying to understand, how
this gut microbiome interacts with timing
of food and then changes the compositional
aspect of the gut.
[Rhonda]: That’s very interesting.
Have you looked at also the short-chain fatty
acids that they produce and whether those
get taken up by the gut [inaudible 01:26:01]?
[Satchin]: So those we are now…so short-chain
fatty acids are little bit difficult to look
at because they are volatile.
They degrade much faster, so those are the
next set of experiments we are doing.
[Rhonda]: Okay, okay.
So does this also suggest we should time our
probiotic intake?
Is there…
[Satchin]: We haven’t looked into that to
see whether the probiotic…
[Rhonda]: Is there any data out there that
has measured…so for example, I’ve measured
my own microbiome using a company called nuBiome
which allows you to send a little fecal sample,
and I’ve done that a few times.
Obviously, now it seems like the time of day
is very important.
I usually do it in the morning…
[Satchin]: Yeah, yeah.
That’s when…
[Rhonda]: …because that’s when…But it
seems like the time of day is very important.
[Satchin]: Yeah, you can capture the compositional
change by time of day.
[Rhonda]: Is there any data out there that
has looked at how the microbiome species change
from morning to evening, like,…
Oh so there is?
[Satchin]: Yes, actually, in humans there
are at least one or two papers showing how
the compositional change also changes throughout
day and night.
And when you have jet lag that messes up the
compositional change.
[Rhonda]: Right.
Yeah, so, you know, very, the…
I think there was study showing that microbiome
gets thrown off and that leads to obesity.
[Satchin]: Obesity, yeah, yeah.
[Rhonda]: Or something.
This is so much, and then of course the shift
workers as well, I mean they’re completely…their
whole system is off whack.
It will be interesting to see whether or not
time-restricted feeding can help negate some
of the negative effects of…
[Satchin]: Of shift work.
[Rhonda]: …of shift work.
Right.
That’ll be very interesting.
[Satchin]: Yeah, so that’s what we are doing
now, to see whether we can put mice in shift
work and give them food within shift or out
of shift.
[Rhonda]: Do you have an option in your app
for shift workers so that you could also get
some human data?
[Satchin]: Yeah.
So, people can say what they…
So in the first sign of a routine, and there
is a question whether you are a shift worker
or a regular worker, and if they say they
are shift worker, then we look at that data
more carefully to see how they are changing
their diet during day shift and night shift.
And also, all shift works are not the same.
Some employers actually put people, change
shifts every week, every two weeks, every
three weeks, and in some cases, every four
months.
[Rhonda: Yeah.
[Satchin]: So we’ll see on the data.
But we are going to introduce another aspect
where they can say when they’re going to work
and when they’re coming back, because there
are now different variations of shift work.
Many of the gig works or flexible shift work
is not even fixed.
So flex hours is a new trend where people
can be called up any time and we want to track
to them more carefully.
So that’s why we’ll have another feature soon.
[Rhonda]: Okay.
And what about…So I know when I filled out
the questionnaire last night, I, you know,
put the city that I lived in.
Is it…so let’s say I’m traveling and I take
a picture of my food, there’s a time stamp,
are you gonna get the time zone, like…
[Satchin]: Yeah, so in the new…it always
tracks the new time zone because what happens
is we thought about it.
It’s a little bit complicated to show two
different time zones and your home time zone,
and the new time zone, but we’ll get to that
to see whether we can introduce that feature
where you can see your data as if you are
in the same time zone.
How your body is adjusting, you can see that
data.
We are working on it.
It’s, time is a very…what we figured out
is time is a very difficult parameter in apps
because as we are moving, as there is daylight
saving time, and all these other time changes…
[Rhonda]: Yeah.
[Satchin]: It completely…displaying data
becomes a challenge.
So that’s another half of the challenge.
[Rhonda]: Yeah, I know.
What you’re doing, but you’re off to a really
good start and I’m really excited about everything
that you’re doing.
I have so many more things that I wish I could
talk to you about but unfortunately, we’re
running out of time.
I know you have another meeting.
You are on Twitter.
I follow you on Twitter.
What’s your Twitter handle?
[Satchin]: Satchin.panda.
[Rhonda]: Satchin.panda is your Twitter handle?
[Satchin]: Yeah.
[Rhonda]: It’s S-A…
[Satchin]: A-T-C-H-I-N dot Panda, as in panda
bear.
[Rhonda]: Right, okay.
And your website?
Um, mycircadian…
[Satchin]: …clock.org.
Yeah.
[Rhonda]: And that’s where people can find
all things circadian clock, all fascinating
research, you giving presentations, and also
they can sign up…
[Satchin]: Yeah, they can sign up, and also
almost every week now we’ll have a blog, either
from a…actually, we are getting our first
blog from a user.
Just like you, this person started before
even our human work was done, and he just
started voluntarily and religiously did nine
hours or eight hours time-restricted feeding
for seven months and documented everything,
so…
[Rhonda]: Oh, wow.
[Satchin]: So that’s going up this Friday.
So we are very excited.
[Rhonda]: Yeah.
I really like your blog.
I was looking over it last night.
It’s very informative.
So it’s a nice, nice job.
Well, thank you so much, Satchin.
I’ve been a huge fan of your work for several
years and pretty much all things that I’ve
learned about circadian rhythm, you know,
I’d say 80% has come out of your lab.
So I’m very excited to have had the opportunity
to speak with you.
[Satchin]: That’s very nice of you.
Thank you so much.
[Rhonda]: I look forward to more research
coming out of your lab.
You seem to be doing some really interesting
things.
[Satchin]: Thank you.
Thank you.