Dr. Satchin Panda on Practical Implementation of Time-Restricted Eating & Shift Work Strategies

Dr. Satchin Panda on Practical Implementation of Time-Restricted Eating & Shift Work Strategies

August 1, 2019 100 By William Morgan


Hello, everyone. Super excited
to be here again with Dr.
Satchin Panda, who is a professor at the
Salk Institute for Biological Science.
And this is actually a round two podcast.
Previously Satchin and I had a really long
and interesting discussion on his research
and how…we talked a lot about how the
body’s internal clock, which is known as
the circadian rhythm,
how that is regulated by the external
cues, such as light, and how the
interaction between light in a certain
part of the brain called the
suprachiasmatic nucleus.
Which is like the master
oscillator, as it’s called, or master
regulator, of circadian rhythm and how
circadian rhythm regulates,
you know, when we’re active, when we
sleep, when we’re awake, when we eat,
things like that. But also we talked a lot
about this other external cue which also
regulates circadian rhythm in what’s known
as peripheral oscillators.
Which are other tissues outside of the
nervous system, such as the liver and the
gut, and how that’s actually regulated by
the timing of the food that we take in.
And that’s where Dr. Panda’s work comes
in, has shed a lot of light on what
this…what’s called the timing of the
food intake and how restricting that
timing of your food intake to a certain
period of time, for example 9 to 12 hours
during the day, can possibly affect a
variety of different metabolic outcomes
and health factors. So his research in
animals has shown that animals that are
restricted to eating within a 9 to 12-hour
window have improved glucose metabolism,
improved lipid profiles, improved
cholesterol, you know, increased lean
muscle mass, decreased fat mass, decreased
fatty liver, you know,
favorable gene expression patterns, all
sorts of, you know, really favorable
outcomes. In addition he’s also shown that
when these mice are fed a…what would be
sort of analogous to, I think, the
standard American diet, which is,
like, high in sugar, high in saturated
fat, just not a really good diet.
If they are restricted to this narrow
timing, you know, feeding window,
which is 9 to 12 hours, they still have
improved markers of metabolism and
metabolic function. Which is really
hopefully in a way because I think it also
indicates that there may be some
possibility that for people that have a
really hard time eating healthy or just
don’t eat healthy, maybe even just doing
this one thing where they… I mean
obviously we want them to eat healthy.
But if they don’t, eat within a certain
time window that’s more restricted
possibly that would have favorable
outcomes. So I’m super excited,
Dr. Panda, or Satchin. So just sort of
since we’re talking about this,
do we have any human evidence that the
people that have, for example,
like metabolic syndrome, if they eat
within a time-restricted eating window,
there’s any benefits to that without
changing their food composition?
Well, historically most of
these research studies haven’t looked at
timing per se, but there was a very nice,
comprehensive review published by American
Heart Association that went back to many
studies where timing,
or at least how many times people ate
during the day, was recorded.
And after compiling all the studies, it
was close to 70 or 80 different studies
related to fasting of decent quality, how
many times people ate,
that found that, yes, limiting food to a
certain number of hours during the day or
maintaining overnight fasting was
beneficial for cardiovascular health.
So that’s a very well done meta-review of
existing literature.
What we need to do now is to look for new
studies where this is specifically looked
at where everything else is kept constant
and timing is changed so that we’ll see
whether the benefit is seen among
individuals who already have metabolic
syndrome. So that’s what is lacking in the
field. And, as you know,
this is a very new area of research and
NIH funding cycle is five years,
so any of the studies will take at least
five to seven years before we see any
result and peer-reviewed journals.
Particular for, I guess, a
clinical trial of actually looking at
someone with metabolic syndrome. Probably
obesity… I mean if a person is obese,
it may take a little more than just
time-restricted eating to lose weight.
Although they may, they may lose some.
They may require more of a,
like, prolonged sort of fasting, but the
time-restricted eating certainly would
affect their… I would predict would
affect their metabolism.
Yeah. So what we see in our
study, a small study that was published,
and also some of the other studies that
may be in the pipeline,
when people adopt a time-restricted
feeding in their regular life,
in real life, not in the laboratory
condition or in clinical trial,
then they naturally reduce their caloric
intake without even counting calories.
So, for example, when they stop, suppose
their target to stop around 6:00,
7:00, or 8:00 in the evening, then the
late night snacks and then the late night
glass of wine or beer that used to be
their usual habit, they stop that.
So in that way they’re doing two things,
one is reducing calories and also
improving nutrition quality because that
extra energy-dense diet is not getting
into their system. So in that way I’m
hopeful that we’ll see some weight loss,
and then some improvement in real health,
blood biomarkers. And in rodent studies
what we have seen when we take already fat
mice, who have been eating a really
unhealthy diet for a long period in their
life, and then put them on a
time-restricted feeding paradigm, they
don’t become, like, lean mice in terms of
body weight. They become overweight, not
normal. But surprisingly they’re
biochemically…or physiologically they’re
more healthy because their blood
biomarkers for glucose, cholesterol,
triglycerides, they come to almost normal
range. So we have to make the distinction
that some people may not lose a huge
amount of weight, but they might actually
see benefits in their metabolism and
physiology. So that’s one thing you have
to look out for.
But this is, the mouse study
you were just referring to,
they were still fed a poor diet?
Isocaloric.
Yeah, okay.
Yeah, they were still fed a
poor diet, isocaloric diet.
So imagine if they were fed a
better diet and…the obese mice were fed
a better diet and they were doing
time-restricted eating.
Yeah, so they
would be much better.
Much better.
They would lose more fat
mass and become much more healthier.
Can you explain for people who
just aren’t very familiar with
time-restricted eating or time-restricted
feeding, as we call it with animal
research, like, just what is that and how
does that actually affect your metabolism
of glucose and fatty acids
and amino acids?
Yeah, so let’s kind of step
back and ask how does it relate to
circadian rhythm, or the daily rhythms. So
if we think of our daily health,
our health, our personal sense of how we
feel healthy changes from time to time
throughout the day. So, for example, in
the morning when we wake up,
being healthy means you’re feeling much
rested and you’re full of energy to start
the new day. You’re feeling actually much
lighter, you should not feel that full
stomach or grogginess, and have a good
bowel movement. And then throughout the
day being healthy means not feeling too
hungry, so having some food in your
system, and then being productive
throughout the day. And then towards the
end of the day being healthy actually
means having taken a walk or something so
you are not feeling really…you haven’t
moved all day and you’re not feeling that
sense of being constrained in a place. And
at night time before going to bed being
healthy means feeling really sleepy, so
that as soon as we switch off the light
and get into the bed we fall asleep. So in
this way you can see that being healthy,
this definition is very different at
different times of the day.
And a lot of it actually has to do with
physiology or metabolism.
So in the morning feeling lighter and not
groggy and not having a food hangover
means you have already gone
through…hopefully somebody has gone
through 10 to 12 or even 14 hours of
fasting, not having food in the system,
so that your body has metabolized all the
food and has processed it and your gut has
also gone through rest. And then towards
the end of the day when you’re going to
hit the bed, if we have food in our
system, what happens is blood flow is
directed towards our stomach to digest the
food and absorb it,
so core body temperature remains high. So
not having food for two to three hours
before going to bed actually helps us to
go have that deep sleep,
sound sleep throughout the night. So in
this way now if we back up and think,
“Okay, so when should we eat?,” then it
makes sense that, well,
after waking up maybe give one or two
hours before we start eating,
and then before going to bed at least
three to four. Depending on what your
metabolism, two to four hours before going
to bed we should stop eating.
So that brings up an eating window of,
say, up to 10 to 12 hours max when we
should be eating so that we have that
personal sense of being healthy throughout
the 24 hours. So in animal studies what we
have done is we ask a very simple
question. If we take animals and give them
food just like most labs do,
they have food in the hopper they can eat
whenever they want, and we calculate how
many calories they eat. And then we take
another group of mice and then give them
the same number of calories and from the
same source of food, whether it’s high
carb, high fat, high fructose. It doesn’t
matter, we have to give the same source of
food, same number of calories to the
second group. And they have to eat all
that food within 8, 9, 10, or even 12
hours. Then we consistently find that the
mice that eat all their food within this 8
to 12 hours window are healthier than ad
libitum fed mice. So that led to the term,
what we call time-restricted feeding,
where the timing of food when we eat is
restricted or you define it and stick
within it. Not caloric restriction, where
you have to count calories and restrict
it. So in this way it becomes very easier
because you just have to…we all know how
to manage our time, on a daily basis we
are always dealing with time.
So it becomes easier because if we start
eating around, say, 8:00 in the morning
and, based on our lifestyle, we can do 10
hours eating, then I’ll have my dinner,
say, around 6:00. So that’s the concept of
time-restricted eating or time-restricted
feeding.
And, yeah, I think that having
the time where you just sort of say,
“Well, I should stop eating by, you know,
6:00,” or, you know,
kind of having it so you don’t have to
constantly each day think about it,
like, “When did I eat my first meal?,”
or,” When did I take my first bite?” If
you kind of just have this general
schedule where it’s, at least during the
workweek, you know, it’s easier.
And then another thing I must
point out, that in our animal experiments,
when we do these experiments, suppose we
say eight hours, we’ve fed the animals for
eight hours. And then every week we
measure their food intake and some weeks
they might eat less. And then we
immediately change that schedule to,
say, eight and a half hours or nine hours
the next week to make sure that they
actually eat the same number of calories.
So moving this needle by one hour actually
is not that detrimental. It still gives
them the benefit. And we have also asked
another question, so in animal
experiments. In weekend we let them free,
they can eat whenever they want. And they
definitely go outside of a 12-hour window,
they eat almost throughout the night. But
still that two days of binge eating can be
counteracted by if they stick to 8 to 9 or
10 hours during the weekdays.
So that also gives us hope that perhaps in
humans occasional eating maybe once or
maybe maximum twice a
week can still be tolerated.
That’s good to know, I guess a
lot of people would be happy to hear that.
Yeah.
What do you do? So for your
typical workweek and then weekend
schedule, like, what’s
your time eating window?
Yeah, so it’s… You know,
I travel a lot, too,
but I…what I’ve found is if I stick to
maximum 12 hours window,
then I actually feel much better and more
energetically, I sleep well,
and I feel lighter, and I’m still
productive throughout the day.
So I start, say, somewhere around 7:00 or
8:00 in the morning,
and then I stop around 5:00 or 6:00 in the
evening. And I also try with different
types of diet once in a while. One thing
with many people who are new to
time-restricted eating, or eating or
feeding, is when they start it they feel
hungry. And what we have found is while
having a fiber-rich diet or a protein-rich
diet or a slightly higher fat-rich diet
actually helps to go through that longer
time without food. And slowly you also get
used to it. And all of these actually
increase your nutrition quality because
you’re staying away from simple sugar and
high glycemic food and you’re leaning more
towards food that takes a longer time to
digest or longer time to absorb. So that
helps. And that way my diet,
both diet quality and also the duration
have changed. And I usually stick to 12
hours, and in many cases I kind of try to
stick to 10 hours.
Oh, me, too. I try to stick to
10. You’re talking about the people
feeling hungry when they first try this
out. Has anyone ever looked at how
time-restricted eating affects satiety
hormones, like leptin or ghrelin,
which would be the one that makes you
hungry?
Yeah, so we haven’t looked
at that in humans, but in mice what we see
is all of these hormone levels that come
back to more homeostatic range,
that means they don’t go too high and also
don’t go to low. So that was kind of
surprising because we thought that the
hunger level will go up and the hunger
hormones might go through the roof. But
somehow after a few days the body adjusts
to it, and then it gets them in a
homeostatic range. And also humans who do
it, we do see that after two to three
weeks the hunger at bedtime is pretty low.
They don’t feel hungry. They might feel
actually lighter and ready to sleep.
So then they realize how it feels like to
go to bed with a lighter stomach than with
a heavier stomach.
Yeah. And then once you
actually, if you break that
time-restricted, you know, eating or
feeding window, I’ve noticed at least in
myself you actually start to feel worse.
Yeah, yeah.
Like right now I’m 37 weeks
pregnant and through my pregnancy I’ve
pretty much thrown, you know, my TRE and
my time-restricted eating out the window.
Well, I do do 12 hours, but usually I do
10, I try to do 10, sometimes 9.
Particular if I’m going to go for, like, a
run in the morning or something that’s
endurance-related, I like to eat within a
shorter time window.
Yeah.
But there are times that I
can’t even do…like there have been time
throughout my pregnancy that I can’t even
do 12 hours and I eat a little bit after
that. And I do notice
it affects how I feel.
Yeah.
Like I feel more lethargic the
next morning.
Yeah. So there’s this food
hangover that stays with you.
It’s almost like, yeah, as if the food
stayed there in the stomach,
it didn’t get digested, or the stomach was
sleeping when the food came.
Right.
And we get that response
from many of our users,
app users, that do say…
From myCircadianClock.
myCircadianClock app. There
are many times when people…
Usually what happens is for the first two
to three weeks people are very diligent,
they try to do it and they get into that
rhythm. And then we get this occasional
feedback. Around week five or six when
occasionally they felt like they could go
out late at night and eat, and then the
next morning they felt horrible because
they were feeling so lethargic, so groggy.
And then they e-mail us saying,
“Wow, really it felt like our stomach was
really sleeping and I’m not going to do
that again.”
That’s interesting.
So it’s kind of interesting
that that hits around week five,
six, seven when people think that they
have adapted to a lifestyle and they are
doing okay and maybe they can occasionally
east outside the window.
And they do that late into the night, and
then the body reacts.
Yeah.
And they recognize
that reaction.
So for people that aren’t
familiar, the myCircadianClock app can be
found on the website myCircadianClock. And
it’s basically you’re crowdsourcing data.
You know, people that want to try this
time-restricted eating out can try it out
and also send their data to you and take
pictures of their food so that you can
gather data for your study, yeah.
So that’s kind of a neat thing,
that people can participate. While they’re
trying this out, why not contribute to
science?
Yeah. I mean what we
realized is even if we get the best funded
clinical trial grant from NIH or DoD or
any funding source, most of the clinical
studies are done with people who live
within 20 to 30 miles radius of a clinical
center. And so in that way, even if we
foresee there will be five or six clinical
trials in this country, there will be only
five or six of those centers.
And people who are living within that 20
to 30 miles and have time and energy to
travel to a clinical center, spend almost
half a day and every two to three months
or two to three weeks will participate in
this study and will see the benefit
firsthand. Then we realized that in that
way most clinical trials which are low
risk like this one actually will
benefit…or will sample a very small
fraction of people. So that’s why I came
up with this idea that if we have a study
that’s approved by our ethics committee
and we make sure that we maintain the
privacy of people, we don’t sell this
data, we don’t share this data with
anybody else, and we give that assurance
up front, then we may be able to recruit
or enlist participants who are not living
within 40 miles who don’t have time to
come to a clinical center, but are willing
to share their data for science.
And they can live anywhere in the world,
they can share their data.
And in this way this has been extremely
useful because, again,
in any clinical trial if you look at the
exclusion criteria, there is such a long
exclusion criteria that only 1 in 50 or 1
in 100 who even shows interest in
participating, they can participate. But
if we take that result and then try to
disseminate to the rest of the people,
those 49 or 99 people who could not
qualify, then how are we expecting that
this would be applicable to all of them?
So it’s kind of a conundrum. So that’s why
we thought let’s try this way where the
only exclusion criteria is if you are
below 21 because that’s NIH’s mandatory
exclusion criteria. And in this way not
only we can see whom it will benefit,
we may also see whom it will not benefit.
So we can actually a priori figure out
what are the limitations of TRE. And
people who don’t qualify,
for example shift workers, they’re mostly
excluded from many clinical studies
because of the nature of their work, they
cannot come to the clinic at the right
time, and this is more relevant to them.
So now we have thousands of people who are
shift workers and they’re trying this. And
from them we are also learning what they
can adapt and how they can adapt this TRE
into their lifestyle and whether it helps
them with alertness being on the job and
whether it helps them to sleep on the
weekend and all that stuff. So that way
this has been extremely useful to have
this kind of study and sometimes we even
get responses from our users that we had
never thought about. So we take that
response and see, “Hey, can we do this
animal study and see what is going on?
What is the biochemical basis for this?
What is the physiological response in
animals?” Maybe that’s how we can
address… For example, there are many
cases there are many immune-related
diseases and people report that this
immune-related disease has improved on the
time-restricted eating. And that is
surprising for us. But then we went back
to our animal data and we realized that,
yes, we actually see systemic inflammation
goes down with time-restricted eating. And
that makes sense. If the systemic
inflammation goes down, then many
immune-related or inflammation-related
diseases would also go down with
time-restricted eating. So there are some
examples like this where our human
participants tell us their story.
And if it is one or two person, we may not
take it seriously. But then it’s 4 or 5 or
10 or 15 people telling us the same kind
of story. For example,
many IBS patients who have irritable bowel
syndrome who have been going to the toilet
for five, six, seven, eight times every
day. They do TRE, and then they
immediately see that the number of times
they go to the bathroom has gone down.
It’s a huge improvement for them. And then
we might hear this story once or twice,
we may not take it seriously. But then if
we hear it 5, 6, 7 times,
then we start thinking, “Okay, let’s go
back to our animal data.” Because from all
these animals we have collected every
tissue that’s imaginable and we have a
freezer full of tissues. And then we go
back and test what might have changed,
what might be changing in the gut, what
might be changing in the intestine,
did the microbiome change, did the
interaction between the microbiome and the
horse change. And that helps us to come up
with newer hypotheses and do more focused
studies. So this has been extremely useful
for people to go sign up on the
myCircadianClock website, and then
download the app and share their data and
also share their experience.
Wow. I just love
hearing…there’s so many things that you
brought up that I have marked in my head
to talk about. But first of all,
to speak to your point, this is really…
I think it is extremely important that
you’re gathering all this data from people
without all these limitations,
aside from the age limitation. Like you
said, you’re getting the shift workers.
I mean this is hugely relevant for shift
work and, you know, people that have IBS,
people that have, you know, multiple
sclerosis. Obviously people that have
certain conditions are probably consulting
with their physician.
Yeah, they do.
But, still, you’re getting
this data, and then seeing these trends
when people start to say these things over
and over. Like, “Oh,
my IBS is improving.” And you hear it
five, six times, then you start to go to
the mouse data and start to do experiments
and tease our mechanisms.
Yeah.
I mean it’s just fantastic,
it’s absolutely fantastic.
So the first thing with inflammation you
mentioned, do you think that part of the
reduced systemic inflammation has to do
with the fact that, you know,
if you’re eating within the
time-restricted window… And this is
something, you know, your metabolism is
optimal during this certain time window.
So the first time you take in food sort of
starts these peripheral clocks on the
liver, for example, which
regulate glucose metabolism.
Yeah.
And if you, you know, don’t
eat within a window where you’re most
insulin-sensitive and you start eating
later, then you’re going to have more
inflammation because your blood glucose
levels are going to rise and it’s going to
cause all sorts of problems. Same thing
goes with, you know, fatty acid
metabolism, right?
Yeah.
And the intake of fat itself
actually can inhibit the beta oxidation
process.
Yeah, yeah.
Right? So, you know, if you’re
eating within this certain window,
you’re affecting your metabolism. And
that, in turn, would then affect
inflammation.
Yeah.
Possibly.
Yeah. So there’s also this
idea that there is some amount of gut
leakiness. And so some of the bacterial
proteins or bacterial membrane component,
for example LPS and a few other things,
can leak through our gut lining into
circulation. And that can illicit immune
response. But we know that with
time-restricted eating, since our gut
repairs itself at night for us,
then during fasting time the gut has
enough time to repair so that the gut
leakiness goes down. So in that way our
immune system is actually less exposed to
these antizymes that might
leak through the gut.
Right.
That’s another way that
inflammation can go down.
I remember a colleague of mine
who his name is Mark Shigenaga.
He was a former colleague of mine when I
was doing a postdoc with Bruce Ames,
he’s a brilliant guy, gut expert. And he
was telling me all about…
I remember him telling me about how the
gut can handle a high fat meal the best in
early in the morning.
Yeah.
Because of all these repair
mechanisms and things that are happening.
Like, the first thing in the morning,
like, it’s better to eat…he was saying
your high fat meal was more…your gut
could handle it better than it could,
like, later on in the evening. So it’s
kind of interesting. But the LPS leakage
and all this, very relevant for
inflammation.
Yeah.
And the gut is one of the
major sources of inflammation.
Yeah.
So the gut, the gut is also,
you know, on a circadian rhythm.
And not just the microbiome, but, like,
the, you know, the goblet cells in the gut
and the ones that are making the gut
barrier. And all these, you know,
all these cells are on a circadian rhythm.
Yeah.
So it really does make sense
that you want to eat within a certain time
window for the health of your gut.
Yeah.
Right?
One’s health starts from
the gut. It’s our interaction,
when we say health is a product of our
nature versus nurture, our environment,
one of the biggest interactions with our
environment happens in the gut through our
food and how the food is digested, how the
microbiome handles that food,
our digestion then sends it to our system.
So that’s actually the interface between
nature and nurture, so what happens there
has huge impact. And we’re actually
finding that the entire gut lining from
esophagus all the way to cecum is strongly
circadian. There are many transporters,
there are many bumps. And even the
channels that absorb drugs and get into
our liver, many of them are strongly
circadian. And over the last two years
there are also many papers that are coming
out showing gut microbiome composition
itself is circadian. So that means the bug
in our system when we go to bed are very
different from…we wake up with a
different set of bugs in the morning.
Right.
And this diversity is much
more important because a different set of
bugs have their own specialization. So
they break down or process different kinds
of food, or they also offer different
kinds of benefits. So in mouse experiments
what we have seen is when mice eat a
standard diet, a healthy diet,
and they eat on a regular rhythm, so they
eat mostly during nighttime because
they’re nocturnal, and eat less during
daytime, the their gut…the microbiome
composition changes nicely in a rhythmic
fashion throughout the day.
But when they eat this high carb diet
continuously, then that diversity goes
down, their gut is mostly populated by a
few meso microbes. And then when they eat
on a TRF fashion, when they eat only for 9
to10 hours, then some of the minor species
that are almost obliterated on that
constant eating, they slowly come back and
they start to work. So we see that
diversity component slowly coming back.
Without even changing the
composition.
Without changing the
composition, so
the diversity comes up.
Wow. Amazing.
Yeah.
That’s amazing. Do you know if
shift workers have a higher incidence of,
like, IBS or gut issues? I mean there’s
certainly a higher incidence of obesity
and metabolic syndrome.
Yeah, so the shift workers
always complain about gut disease.
So gastrointestinal problem is the first
thing they always report/complain about.
So it makes sense from our mouse study and
also from what we know from shift workers,
that circadian rhythm or circadian eating
pattern will have a huge impact there.
Yeah, so it makes sense. And
what we know from how the gut microbiome
also affects the way we’re absorbing
nutrients, it would affect obesity,
as well, right?
Yeah.
So that’s been shown. So maybe
there’s also a link to that.
So I think on a daily
basis, like for example on a daily basis
what would healthy, another definition of
healthiness while going to be bed at night
is not to have this acid reflux or
heartburn. Which is essentially a gut
sodium…sorry, the proton pump working
differently. And what we find in mouse
studies is this expression of the level of
this proton pump goes down on the
time-restricted eating. So this is one
example where many of our myCircadianClock
users reported saying, “Oh, well, you
know, the first benefit we found is our
acid reflux has gone down, we don’t get
that much heartburn.” And then we got
curious, we went back to what are the
targets of all the acid reflux drugs,
and we found this proton pump. And
interestingly this proton pump expression
goes down in mouse gut.
That’s awesome. That is so
awesome.
So this is another example
where we would never ask about…we don’t
have even the means to ask what is acid
reflux and heartburn in a mouse,
but we have a means to actually get this
response from users and go back and ask
the mechanism in a mouse.
Yeah, it’s great. I’ve
never…the first time I experienced acid
reflux was during my pregnancy, late
pregnancy, when my husband and I went out
and had some, like, fancy meal.
And I usually don’t ever, like,
eat sugar or dessert, but I had, like, a
little thing of, like,
ice cream with some, like, chocolate or
something. And we were in a hotel,
and then, like, we went to bed not long
after. And I could believe how
unbelievably painful and uncomfortable it
was because I’ve never had it in my life.
Apparently when you’re pregnant, it’s a
problem because, you know,
your stomach is getting…
Yeah, squished.
…squished. But, anyways, I
decided at that moment I’m like,
“I’m not eating out like that again,”
because I don’t want to experience it.
But just I’ve heard about so many people
talking about acid reflux before and I
never really knew. I was like, “Oh,” you
know, “So what? What is it?,” like,
“Your stomach is upset.”
Yeah.
No, you can’t sleep.
Yeah.
It’s, like, burning.
Yeah.
It’s like something is coming
out burning. It was awful,
I had to, like… I could sleep, I had to
sit up for, like, a couple of hours.
So that, you know…the fact that TRE
seems to be affecting, you know,
acid reflux, you know, through this
specific proton pump inhibitor in some
people using your app is,
like, super cool.
Yeah.
The shift work is…so back
to, like, the shift work and stuff.
Because a lot of people have reached out
and asked that are…
I mean I think it’s something like 20% of
the U. S.are shift workers,
is that right?
So in the U.S. 20% of the
workforce is shift workers,
but at the same time there are many who
are…who may be shift workers,
but they are not counted in the Department
of Labor Statistics.
Like who?
So, for example… And
nowadays you can include the taxi drivers
or Uber drivers or Lyft drivers because
they don’t classify themselves as shift
workers. They might have a one regular job
that they list, but then in the evening
and weekends or early morning they are
kind of doing the second gig and they
don’t list themselves. Then another thing
that we came up with is what we call
secondhand shift workers. So these are the
family members of shift workers who have a
lifestyle that are very similar to shift
work. And this is something that we found
in a study, in the same myCircadianClock
study, in India where we found some people
who self-describe them as not shift
worker, but then their eating pattern was
like shift workers. So when we asked them
again, then we realized that their spouses
were shift workers. And to maintain that
strong family bond they wanted to share
meals with their shift work spouse, shift
worker spouse. So in that way we call them
the secondhand shift worker who are not
working in shifts, but they are actually
sleeping and eating like shift workers and
they may be experiencing the same adverse
metabolic consequences of shift work.
Right.
So in that way the actual
number of people, fraction of population,
who are experiencing shift work-like
phenomena for a few months or years in
their lives may be upward of 30% or 40%.
Wow. That’s a lot of people.
That’s a lot of people.
Because in India and China, the
card-carrying shift workers in the
workforce can be around 27% to 30%.
And then a fraction of them have family
members who are like shift workers because
they’re secondhand shift workers. So it
can be upward of 30%.
And some of the negative
consequences that are pretty,
I would say, scientific consequences
that’s associated with shift work,
what would be, like, the top
few that you would say?
Yeah. So cardiovascular
disease is right on the top.
And then obesity, diabetes. And actually
the very early study on shift work and
metabolic disease was linking shift work
with diabetes and obesity.
And then slowly we started to see that in
many of the longitudinal studies with
nurses or with health professionals, just
random eating patterns and shift work
increases cardiovascular disease risk. And
then recently I came across this very
interesting piece of data that I was not
aware of that the number one cause of
death and disability among firefighters in
the U.S. is not actually related to fire,
it’s cardiovascular disease and stroke. So
that’s the number one cause,
not even firefighting fire. So that tells
us that all these chronic diseases are
linked to shift work. And then there also
is mounting evidence all over the world
that shift work is tightly linked or
increases the risk of certain kinds of
cancers, including breast cancer. So
that’s why World Health Organization has
categorized shift work as a potential
carcinogen. So that’s a very serious
classification because if we know that we
have to stay away from carcinogens,
even in buildings, if there is a
carcinogen, there’s a potential carcinogen
used as a paint or there is a reason, then
we have to put a sticker.
And to think about shift workers, they are
actually doing something that’s a
potential carcinogen. They do it almost on
a daily basis for many,
many years. So that’s why I think now
there is increasing awareness how to
manage shift work so that they will stay
healthy and will reduce the risk of
disease.
And they’re doing something
beneficial. I mean firefighters,
nurses, you know, police. I mean they’re
helping society, so it’s not like you can
just eliminate shift work, right? I mean
you need shift work.
No, actually our modern
society is actually based on those heroes.
So we actually call them the guardians of
our society because they are the ones in
the middle of the night, they are making
the economy running, they are the ones who
are hauling trucks, long distance trucks,
and they are the ones who are actually
transporting cargoes of a plane or ships.
They are the ones in the middle of the
night that are taking care of our health
and to any emergency.
So we have to kind of make sure that these
heroes are healthy.
So we have to kind of start thinking how
to come up with a healthy heroes program
where we can clearly say these are the
lifestyles that they can adopt in relation
to their being productive at work so that
they stay healthy. And one complexity with
shift work is shift work is just not one
type of shift, it’s a mixture of many
different types of shifts. And, for
example, firefighters may be on shift for
24 hours straight, whereas a nurse is on
shift for only 12 hours.
Some of the fast responders may be on
shift only for eight hours.
And then for them, for some of them, the
shift might change two or three times
within a month, so they may be on a day
shift versus night shift,
even within the same week. Whereas in some
departments and in some professions they
can be on the same shift for three to four
months, which helps them to adapt to that
shift. So in that way I think it will be
interesting to bring up this heterogeneity
in shift work and figure out which kind of
shift work is more manageable than others
and perhaps figure out how we can help,
firefighter kind of shift work versus
nurse kind of shift work
and first responders.
Yeah. Do we know from any
animal evidence… For example if you take
an animal that is, you know, for example,
nocturnal, like a rodent,
a mouse, which usually eats at night, you
force it to now not eat at night but to be
awake during the day and eat at day and
not eat at night. So if you can shift them
to not eat all day, all night, but eat
just within a time-restricted eating
window, do we know if they eventually
adjust, how long it takes for them to
adjust? Does their metabolism adjust? Does
their circadian rhythm adjust?
Yeah, so those studies have
been done and there are many different
ways to look at it. One is if we just give
the same unhealthy high fat,
high sucrose diet, instead of giving them
at nighttime for 10 hours,
for example, give them during daytime when
they’re not supposed to eat,
when they’re supposed to sleep. So the
bottom line is if mice eat randomly,
then any kind of time-restricted eating is
better than that random eating.
So even if they eat during daytime for 10
hours, that still gives them some
benefits. So it’s still beneficial. So
there are some concerns with animal
experiments. One is if we feed animals
during daytime, definitely they lose some
sleep and they just eat. Unlike shift
workers, they’re actually not working
throughout the daytime, unless we force
them to really work. So then it becomes a
two-factor intervention. And then at
nighttime when they actually go back to
their normal activity, they run around in
the cage. So in that way they get a sleep
deprivation pattern factor into it. So
they are not as healthy as night-fed mice,
but at the same time they have a strong
sleep deprivation factor.
So that’s why I think among shift workers,
coming back to shift workers,
if we can control for how much they sleep
during their off time and they can sleep
enough, if they come up with some sleep
hygiene and adopt some sleep rituals that
help them, and then they adopt the eating
pattern that best suits their shift,
then it might help.
But eating still within a
small, more narrow window.
Yeah, still eating within a
narrow window. Then there is another piece
of [Inaudible] evidence that
daytime eating of healthy food is still
beneficial. And that comes from the area
of caloric-restriction studies in rodents.
So historically many caloric… CR studies
in rodents are actually done in a way
where the CR mice got their food during
daytime. And in most [Inaudible]
the animal technicians come around in the
morning, and then they see our mice get
their food around 7:00 or 8:00 in the
morning, and sometimes even after 9:00 or
10:00 in the morning. And the
caloric-restricted mice actually eat all
of their food within two to three hours.
So they eat. The CR mice
So they wake and just eat
because they’re hungry?
Because that’s when they
have food, access to food,
because the animal techs actually give
them food. And so they don’t sleep
throughout the day and in the evening they
eat, they actually eat right away.
So we know from CR studies that all CR
animals, most of the CR studies in rodents
show tremendous health benefits, even
though they eat the food during daytime.
Wow, I didn’t realize that was
done that way.
Yeah.
So maybe another layer of
complication could be not only just
time-restricted eating,
but eating less, as well?
Well, so one caveat is in
the CR study the ad libitum fed mice were
fed ad libitum, so that means
they were eating at nighttime.
Oh.
So they were never
controlled to eat during the daytime.
Oh.
So I think those are the
new type of studies that need to be done.
But at least we know that if the animals,
we reduce calories and fed them during
daytime when they’re supposed to sleep, it
doesn’t have any adverse impact,
it actually gives them a lot of benefit.
Now the question is if we give them the
same number of calories as ad libitum fed
mice during daytime,
what happens? And we have done that
experiment not with a standard diet,
with a high fat diet. And with a high fat
diet they are better than ad libitum fed.
Right, right. So, okay.
So I think for shift
workers, if they can constrain to a
certain number of hours, that’s better.
They can improve nutrition,
that’s still better. They can reduce
calories, then that will be,
again, better.
And if they couldn’t sleep,
maybe do things to help them sleep better
during the day.
Yeah, during their off
time.
You know, dark, quiet, cool,
all the things that help you sleep.
Yeah.
So there is sort of some hope
possibly, possibly for shift workers.
And maybe, you know, as more data comes
out through your study with
myCircadianClock and also as you get data
from myCircadianClock app and then go to
animals and look more mechanistically,
things may come out even more.
Another sort of question that sort of
relates to this is, and people ask this
all the time, is what about people that
are…start eating later in the day?
For example they wake up 8:00 in the
morning, but they don’t eat until noon.
So let’s say they eat their first bite of
food at noon, and they stop eating at
8:00 p.m. So that’s an 8:00 TRE eating
window. And they go to bed by 11:00 or so.
Do they still have the same benefits or
are they losing because it’s like the
time-restricted eating window has kind of
shifted to later and obviously there is a
light/darkness component to all this to
some degree?
Yeah, yeah. So those
questions we haven’t even teased them in
animal models, but I’m sure some people
will start teasing them apart.
So what happens is in the morning we know
insulin sensitivity is at its best.
So people who have a bigger meal earlier
in the day, they have less insulin spike,
less glucose spike, etc. Having said that,
we don’t know for people who are starting
their food every day at noon whether
they’re best insulin sensitivity is at
noon or it actually happens at 8:00 in the
morning. So that information we don’t
know. So this is where some studies need
human volunteers who are doing this.
And maybe some people who are doing…who
are starting to eat at noon,
one day maybe they can drink a glass of
juice at 8:00 and prick themselves and get
a glucose reading and monitor themselves.
And then another day,
a week later at noon, they will eat the
same glass of juice and prick themselves
and see how is their glucose response. So
that’s a simple self-experimentation with
some healthy people. If they’re out there,
then they can do that.
And if they post it, that will be really
nice. Second thing is what happens toward
the end of the day at night. So this is
where it becomes a little bit complicated
because, as you said, there is day and
night transition. And we know that in the
evening as our body prepares to sleep, our
melatonin level begins to rise.
And that melatonin usually rises two to
three hours before our habitual sleep
time. So if somebody is going to bed
around 11:00, then that melatonin is
beginning to rise around 9:00. On an
average, but some people it might rise
around four hours early and some people it
will rise exactly at bedtime.
And when melatonin rises, there is new
data showing that melatonin can bind to
its receptor in the pancreas. And this
engagement of melatonin with the pancreas
receptor essentially tells the pancreas,
“Okay, it’s time to sleep,
you don’t have to bother releasing
insulin.” So in that way what happens if
somebody is having a big meal when there’s
high melatonin, then there may not be
enough insulin to release from the
pancreas and glucose may stay high in the
blood circulation for a long time. And
this study…these kind of studies came to
publication because almost 10 years ago
large genome-wide association studies
found that people with obesity or diabetes
might have a mutation in melatonin
receptor. And that was confusing because
what has melatonin to do with obesity and
diabetes? And you fast-forward 10 years,
people went back to the drawing board and
looked at where the receptor is expressed
and what it does when melatonin is
engaged, and then they found out that
there is this effect of melatonin on
insulin. So that’s why people who are
eating late into the night,
they may not get the best benefit in terms
of glucose control because their glucose
might remain slightly higher than if they
had the same dinner two hours earlier.
If they’re making more
melatonin.
If they’re making
melatonin. So it’s very…so that’s why I
said it’s complicated.
Yeah.
But at the same time I
would say eating randomly over 12 hours,
15 hours, versus eating to this 8 hours,
even though it starts at noon,
I will prefer the 8
hours starting at noon.
Right. So it seems like
there’s, in addition to, you know,
the timing of your food intake, so we know
the first time you’re eating sort of
starts a lot of these liver enzymes and
metabolism…glucose metabolism and all
these things. In addition to that, that
circadian rhythm being regulated by just
the food intake, there’s also this whole
melatonin issue and the night-daylight
cycle and, you know, when you’re starting
to make more melatonin.
And all that complicates things, as well.
Yeah.
It seems. Yeah, I remember a
study that was done where I think men were
given the same caloric meal in the morning
and the evening.
Yeah.
And glucose was measured and
the blood glucose levels were much higher
in the evening versus morning. But, of
course, they could have been.
Who knows how long… You know, was the
morning, like, 8:00 a.m.
, and then they were doing, you know, 9:00
p.m.or 8:00? So who knows what their
timing window was, right?
The habitual meal, what is
their habitual meal?
Right.
That’s a very widely
observed phenomenon. In fact,
there was a term for that that was called
evening diabetes. So a person might be
healthy in the morning based on blood
glucose. In the evening if you do the same
postprandial glucose tolerance test and
then look at the glucose level,
then maybe diagnosed diabetic.
Right, right, yeah.
Yeah.
Well, I think the other
component to this would be the fasting
component, right? So people think, “Well,
I’m only eating within an eight-hour
window, so I have a much longer fasting
period.” And I think that’s maybe
uncoupling some of these differences
between time-restricted eating,
being on a circadian rhythm, and fasting,
intermittent fasting,
prolonged fasting. You know, there’s so
many different terms out there.
Yeah.
And I think sometimes a lot of
it just all gets mushed together in one
group and it’s, like, all the same.
Yeah.
But it’s not
actually all the same.
No, it’s not the same. So,
for example, even not having food in your
system for 12 to 16 hours, whether it’s
fasting or not, that’s debatable.
Because some people say, “Well, it’s not
fasting, it’s not having food for 12
hours.” And I think that’s where I would
say not having food for 12 to 16 hours is
not fasting, but maybe giving rest to your
system, rest and repair and rejuvenation
of your system. So when we think about
fasting, or when you think about fasting,
two things come to mind. Feeling hungry.
And feeling hungry has many different
connotations, many different intensity. So
one sense of feeling hungry is,
well, you might feel light. And then
second, your stomach may begin to frump a
little bit. And then I always say that is
your stomach is telling you,
“Well, I’m repairing myself.” You’re not
actually really hungry,
you’re not getting low energy that you
cannot get up from the chair or run or
something like that. And then after
several, maybe one or two,
days of fasting, or maybe after 24 hours
of fasting, some people will get a head
ache. So that’s a good sign that, well,
your brain is not getting enough energy in
its habitual usual form and may be trying
to signal the rest of the body that the
body has to send some other form of
energy, for example ketone bodies or
something. So in that way fasting, if
you’re measuring fasting or you’re
defining fasting in terms of ketone body
formation above a certain level,
then that may kick in after 24 hours. Or
if you have that threshold even much
higher than fasting, maybe 20, 48, or 72,
or even 96 hours before you see that level
of ketone bodies that can be your
definition of fasting. So in that way I
think the way you define fasting will
determine whether 24 hours,
48 hours, 96 hours, or even 12 hours or 16
hours is fasting. But the way we think,
we kind of define how many hours your
system should not have food is based on
our daily circadian rhythm. Because if you
think about what are the key elements to
being healthy, it boils down to three
important things. One is sleep,
and the second one is nutritional food,
and the third one is physical activity.
And these three are interlinked with each
other. So, for example,
if somebody is sleep deprived or didn’t
have sleep, then it’s very hard for that
person to do physical activity the next
day or go on a marathon.
So these two are interlinked. Similarly,
if somebody is eating for 15,
16 hours and has a very heavy meal at the
end of the day, then it affects sleep.
It also affects physical activity. One
cannot run with a full stomach.
So these three are interrelated. So on a
daily basis what we feel is
having…limiting food to 8 to 10, or
maximum 12, hours helps to coordinate
these three foundations of health to work
on a daily basis and give us healthy
benefit. So on a very simple sense if I
want to relate time-restricted eating and
then maybe long-term fasting, one day of
fasting, two days of fasting,
or four days of fasting, which definitely
have much more benefit,
then it’s almost like taking care of your
teeth. So brushing every day is like
time-restricted eating. There’s the
minimum one can do and that’s something
necessary to take care of your teeth. But,
again, once in a while,
maybe twice a year or three times a year
or once a year, depending on how much you
want to take care of your teeth, you want
to go see a dentist.
So that’s almost like a prolonged fast one
has to do once a year.
So similarly I do four to five days of
water fasting only once a year and that
absolves all the other sins with my
feeding that I might have committed
throughout the year. So in that way I
think the difference between
time-restricted eating and other forms of
fasting is one can adopt time-restricted
eating as a true lifestyle, starting even
from teenage or even toddler years,
all the way through when you are 80s, 90s,
or even 100 years old.
Whereas this long-term fasting, two days
or four days of fasting,
forget about even teenagers doing it. And
some older people who are very fragile,
they might not be able to do it. And you
need medical intervention or some kind of
supervision to do it. Many people who are
slightly unhealthy, even some diabetics
who might go hypoglycemic after 10, 12
hours, type II diabetic I mean,
they may not be able to do it without
medical supervision. So although those
long-term fasting definitely have much
benefit, and that has been shown in
multiple studies, the need is that they
can be practiced only by a certain type of
people at certain days and need more
mental resolve. And it may not be an
everyday lifestyle, whereas
time-restricted eating can be an everyday
lifestyle.
That’s a great way of putting
it. It sounds like also you’re saying,
depending on what you’re looking at, what
biomarker you’re looking at downstream,
that also can sort of define something
differently. For example,
if you’re looking at autophagy or
apoptosis that’s happening, you may not
see or be able to even measure it. Maybe
it’s happening, but you can’t really
measure it well until you’re getting a
more prolonged fast, like when you don’t
eat for four days.
Yeah.
Whereas, you know, obviously
when you’re not eating for 16 hours,
if you’re doing a time-restricted eating
schedule of eating within eight hours and
you’re fasting every night for 16 hours,
you’re in a fasted state in a way.
I mean maybe it’s not fasting, but, you
know, you’re liver glycogen starts to
deplete at, like, 10 hours of not eating
and, you know, something like this.
And your, you know, adipose tissue is
releasing fatty acids and,
you know, you do start making some ketone
bodies. You wouldn’t necessarily be in a
high level of ketosis or anything, but,
you know, protein deacetylation starts to
go down and, you know, these NAD levels
rise.
Yeah.
So it’s like depending on what
you’re looking at, I mean these things do
start to happen, like in between meals
even.
Yeah.
So to some degree you can be
in a fasted state, maybe,
and not be necessarily fasting.
I mean it depends on where
you set the threshold and whether people
can reliably measure that, say, ketone
body or even autophagy level when beyond
that threshold. So what used to happen was
most labs, the vast majority of labs,
they’re not circadian labs. And many of
the postdocs and grad students and kind of
really the ground soldiers who are driving
science, they might have different
schedules. So what happens, they come to
the lab at different times,
and then they might be doing the assay at
different times without any control of
when the animals were fed or how long they
were fed or what type of food they had
access to. And then even if the mice had
12 hours of fasting or 16 hours of
fasting, one might get a result which is
slightly higher than what it was without
fasting with food. But it’s no
reproducible because, as we know in
circadian rhythm, the same parameter can
change over time. Even if we measure just
fasting insulin level in mice, for
example, or fasting glucose level,
that has a very slow, very small change.
So in many cases people might discount it
as noise in their system because somebody
did the experiment in the morning,
someone did it in the evening, their
bellies are different, so they’ll say,
“This is noise.” So that’s why people have
come up with the longer fasting to see the
threshold to set a higher threshold that
they can reproducibly say,
“This is signal,” irrespective of what
time of the day the postdoc or grad
student did the experiment.
Right.
But then in the circadian
lab what we do, we systematically…we are
very careful about timing. So we will
sample every one hour, to hours,
three hours the same animal over multiple
days, one day, two days,
or even sometimes three days. And then we
ask a very simple question,
“Does it rise reproducibly every day
around the same time?” Suppose,
say, the ketone bodies do rise. And they
may not go from 0 to 100,
but they go from 0 to 10, every day they
go from 0 to 10. Then the second question
is, “What is the benefit of ketone bodies
going to 10 from 0 on brain function or
muscle function or heart function?” It’s
possible that maybe your brain may not get
much benefit, but muscle and heart are
getting some benefit. And in that way you
can see that if we carefully monitor and
then ask specifically what are the
benefits, you can come up with ways where
we can say even this 12 hours of fasting,
or not having the food in your system,
will create some amount of benefit for
heart on a daily basis or some amount of
benefit for muscle on a daily basis.
So that’s why it becomes very difficult,
what is fasting, what is autophagy,
can we trigger autophagy only by 12 hours
fasting or 16 hours fasting,
versus 4 days of fasting. Because
autophagy may go from 0 to 10,
it might benefit only one or two organ
systems, it might benefit 10 organ
systems.
Does it go from 0 to 10? Like,
for example, when…
Yeah, so autophagy, we have
actually published papers showing that
autophagy flux and autophagy gene
expression does cycle on a daily basis.
And it’s directly regulated by some of the
clock components. So mice,
genetically and mutant mice, that don’t
have these clock components,
autophagy level is set high, or the
autophagy level is set low,
depending on which
component will turn up.
Does it go up during the
fasted and/rested period?
Yes. It does go up during a
fasting phase in liver.
In liver?
Yeah.
That’s really cool. So the…
I kind of got sidetracked here with this
autophagy because I’m very interested in
it. Because it’s a part of the repair
process.
Yeah.
And the thing that’s so
interesting is this repair process being,
you know, in the fasting state and, you
know, happening during the fasting state.
And, like you said, maybe there’s a
threshold where, you know,
it’s like obviously if you’re fasting for
14 or 16 hours every single day because
you’re eating within a time-restricted
eating window, that’s also going to have
benefits. And now the threshold may
be…you know, you may have less of those
benefits, but you’re not cleaning up. You
know, you don’t have widespread apoptosis
happening where you’re killing off all the
damaged cells, but you may be clearing up
some protein aggregates or something, you
know, every day sort of on this steady
state sort of level, which also is
extremely important.
Yeah, it’s almost like, you
know, if you have a carpet,
if you vacuum it every day or every other
day, then that remains clean.
But at the same time maybe once a year you
need a deep clean, a wet vacuum.
Right.
But if you don’t do that
daily vacuum, or at least once in two days
or three days, then that gunk will
accumulate.
It’s going to accumulate and
it’s going to cause damage.
Yeah. So that’s why this
daily cleaning, even though it’s a low
level, very low level cleaning of the
system, that has a huge impact,
that goes a long way.
Have you guys ever looked at,
like, DNA damage or repairing any sort of
challenge? Like if you irradiate… Like
animals that are eaten,
you know, on a time-restricted, you know,
feeding sort of schedule where they’re
eating their food, being fed their food,
you know, within 10 hours or so,
and then challenge them.
With radiation or
something?
Can they, like, repair the
damage better because they’re fasting
longer?
Yeah. So the circadian
clock itself has a huge impact on DNA
damage repair and radiation damage repair.
So a few years ago we had done a simple
experiment that got highlighted in
National Cancer Institute website.
There’s a very simple, straightforward
experiment. We always asked…we asked a
very simple question, that is, “How come
humans’ skin is always exposed to sunlight
or UV radiation and many people get skin
cancer but they never get hair cancer?”
Because a hair follicle has the most
rapidly dividing cells. And so one would
expect that they must be most sensitive to
radiation damage. And if there is any
radiation damage, that’s where the tumors
will start. And we rarely see that.
So we went back and checked and we
realized that the hair follicles at the
base of the hair actually have a very
strong circadian rhythm.
And every evening that circadian clock
repairs all the damaged DNA and makes sure
that the hair can grow back the next day,
next morning. And then we asked,
“So what is the real significance in real
life?” So we took these mice and then did
a simple experiment. That is, you know,
for many bone marrow transplant
experiments, mice are irradiated, and then
their bone marrow is depleted and one can
put the new bone marrow in. And they get
irradiated to the same extent as humans
do. They don’t die, they actually survive
pretty well. And if we irradiate mice in
the morning, 8:00, then those mice lose
85% of their hair. And if we irradiate the
same mice with the same dose at 8:00 in
the evening they retain 85% of their hair.
So it’s a big, like really, black and
white difference because these morning
irradiated mice essentially become bald
very quickly. And the evening irradiated
mice, they keep their hair perfectly fine.
Now if we take circadian clock mutant mice
where the circadian clock is absent,
irrespective of what time we irradiate the
mice, they always lost hair. Of course the
story was much more about what…which DNA
repair enzymes are regulated by clock and
how this clock works,
but this is a very simple, straightforward
experiment. And similarly people have also
shown many patients do go through partial
hepatectomy. Or people who have liver
cancer, part of the liver is resected, and
then the liver grows back.
And, in mouse experiments at least, if
partial hepatectomy is done in the
evening, then those mice recover much
faster than those where the hepatectomy
was done in the daytime. So that has
inspired some people to think about this
surgery time, what time surgery should be
done and/or radiation should be done.
So these are some just new ideas that have
just come up in animal models in the last
five to 10 years, so it will take some
time to really get some traction in human
studies.
Yeah. It will be interesting
to figure out whether it’s,
you know, the combination of is it because
they’re, you know, getting more rest
during that time, during the evening, and
then they’re resting,
fasted and resting, and so, you know, the
combination of them all.
Yeah. So we know that the
tumors grow slower in mice that eat only
within certain times. So time-restricted
fed mice, if we just implant a tumor,
then the tumor will not grow as much as
the mice that eat randomly the same number
of calories.
Wow.
And that also jives with
another piece of data that came from Ruth
Patterson’s group that women who fast for
13 hours overnight are protected from
breast cancer.
They have, like, a 36% lower
breast cancer occurrence.
Yeah, yeah.
Yeah. So that’s really cool. I
wonder if with at least the animal
experiments where you’re implanting the
tumor and they’re fed at a time-restricted
feeding schedule, then if they’re having
more apoptosis, more autophagy,
more DNA repair, all these things are all
sort of simultaneously happening because
they’re in a fasted state for longer?
Yeah.
Possibly?
So it’s possible.
Yeah.
Yeah.
Very cool and interesting. The
other thing that is sort of on this whole
fasting versus TRE topic that gets asked a
lot that I have to ask you has to do with
coffee. Actually, specifically caffeine,
like black coffee. So without any cream or
any calories or anything like that. So
caffeine can start things,
like the clocks in your liver?
Yeah, it resets the clock.
Because the clock is always running,
it just resets.
It resets it, okay. So a lot
of people in the intermittent fasting
community, they do a lot of fasting,
whether, you know, they’re fasting for 16,
24 hours, 48 hours, but they drink
caffeine and they notice that they lose
weight. And so they say, “Well, I’m still
getting results.”
Yeah.
You know, “So it’s fine, I can
drink my black coffee.”
Yeah.
You know, obviously someone
that’s fasting for 48 hours,
it’s very different than doing the TRE
schedule where you’re eating for 10 hours
a day or 11 hours a day, and then fasting
for, you know, 13 or 14 hours every night,
right?
Yeah.
So if a person, for example,
that wakes up in the morning drinks black
coffee at 7:00 a.m. They wake up, have
some black coffee at 7:00 a.m.
But they don’t eat anything, they don’t
eat their first bite of food until…
10:00 or 11:00.
Yeah. Yeah, something. Then
when do they have to stop eating by?
Like, is it when the coffee started or is
it when they ate the food?
Yeah, so this is a question
we also get through the app a lot.
And we actually posted a blog on our
website. So here is a very different
thing. So since we look at circadian
rhythm as a whole, it has a sleep
component, food component, exercise or
activity component. And we know that
caffeine resets the body clock. So, for
example, drinking a cup of coffee is
similar to having exposure to bright light
for an hour or hour and a half.
So that’s just on the circadian clock
itself. Now the question is,
“Well, will it reset that clock the same
way if the coffee comes in the morning
versus evening or night?” And we know that
there is a term called phase response
curve. So that means the same light, it
relates to light. The same light will
reset the clock differently at different
times of the day. During daytime when your
system is expecting light, if you’re in a
dark room and we see light it doesn’t
reset our clock. But in nighttime it will
reset our clock. So we don’t know what is
the phase response curve for coffee,
whether it resets much more at certain
times and less at other times. The direct
impact of coffee on clock is unknown.
Then the second thing that relates to
coffee is sleep because coffee definitely
suppresses sleep in a lot of people, some
people may be resistant.
And the reason why we drink coffee is we
wake up, we get up from the bed,
but we maybe are still feeling sleepy. We
want to get that extra energy,
that’s why we drink coffee. And along that
line, of course, drinking coffee at night
is a straight no-no because it will have
impact on sleep. But in the morning we ask
the other question, “Are you drinking
coffee because you did not rest well,
you did not rest enough?” So maybe that’s
why you need coffee to reset your mental
clock, or brain clock, to start it. And
sometimes it can be just a pure habit or
addiction. For example, I used to like
coffee in the morning, and then I
realized, “Well, let’s get rid of
coffee. What happens?” Maybe for
the first two or three days I got a
headache, and then now I’m used to
drinking just hot water. It’s just the
feeling of sipping something from a sippy
cup. It’s almost like a baby sipping
something from a sippy cup.
And I realized that that’s what I was
addicted to. I can actually substitute
coffee with hot water and nothing changed.
I still felt energetic after my hot water
and I realized that that was my addiction.
After you got over the…
After I got over the first
two days of headache.
…withdraw.
Yeah, withdraw symptoms.
And then it’s always [Inaudible]
the question of metabolism. When we drink
coffee, is it going to trigger metabolism
or certain things in our gut so that the
gut will think, “Well,
now I have to start working, the rest is
over”? And we think that’s where the
metabolism or the function of the gut to
absorb, or digest this coffee,
send that caffeine to liver, and then to
brain does kick start right after we drink
coffee. Because that’s how we are feeling
the effect of coffee in the rest our body,
because the stomach started working, it
absorbed coffee, it sent it to liver,
liver might have metabolized it slightly
and started to send it to the rest of the
brain and body. And then it gets back to
kidney, it gets metabolized and excreted.
So then the question is, forget about
circadian clock, now if we think about
just metabolism and, say, mitochondria
function, or even, say,
go back to autophagy, and then ask, “Is
caffeine breaking the fasting so that it
stops autophagy, or it stops something
else? Or is there a crosstalk between,
say, caffeine receptor and glucagon
receptor so that it does?” No,
fasting is kind of slightly over. You may
not be in 100% fast,
but in 40% or 50% fast. So that’s where
things become murky, so that’s why we say,
“Well, if you can, drink your coffee
within this 8-hour, 10-hour,
it’s better.” But at the same time we
know, going back to the study that we
discussed, Ruth Patterson study, they did
not consider coffee as food.
So when they considered 13 hours overnight
fasting, that 13 hours actually included
coffee and tea. So in that we know for
cancer, reducing breast cancer risk,
this 13 hours of fasting can include
coffee, black coffee, and tea.
So this is where things are really murky.
And we tend to error on the safe side,
so we tell, well, if you can have that
coffee within your eating window,
that’s much better. If you can’t, then
just have black coffee.
At least that will not trigger your
insulin response or glucose response.
So that’s what we do, we recommend.
Just sort of as a side note
because you mentioned it,
I recently spoke with Dr. Guido Kroemer,
who is an expert on autophagy,
and he was telling me about a study he had
published a few years ago where the
specific polyphenols in coffee, decaf or
caffeinated… So irrespective of
caffeine, it’s just it’s the polyphenols.
Yeah.
They triggered protein
deacetylation, which is one of the
triggers for autophagy. So it actually
increased autophagy.
Increased autophagy, yeah.
So that’s why we never know,
because coffee, or any natural compound,
has so many different ingredients that we
don’t know the activity.
Yeah.
And many of them can have
very different effects.
When we think of food, we have
mostly…the nutrition science,
or most of the scientists, are latched
onto the effect of protein,
carbohydrates, and fat. We discount a lot
of xenobiotic. And actually our food is,
the majority of it is xenobiotic.
Right.
And we have no idea what do
they do, either alone or in combination.
Right. And that
actually…that’s another question.
I printed out some, but that is a question
that’s frequently asked by people in the
audience. Is, like, things that are
xenobiotic, like herbal tea,
even, I guess, to some degree people are
asking about flavored water.
So water that would contain, for example,
like or stevia or something,
you know, does that start the clock? And I
think you’ve kind of answered that a
little bit.
Yeah. So in that way it may
not stop the clock and,
also, for your insulin response it’s not
actually triggering the pancreas to
secrete extra insulin. You know, insulin
is an anabolic hormone,
so it’s not actually putting our body into
a strong anabolic drive.
So in that way, in many ways, it’s okay to
have this non-calorie-containing food.
But then it gets murkier once we go to,
say, Diet Coke or something else where
there is artificial sweetener, and then we
know that the artificial sweeteners have
an impact on gut microbiome. And that’s
where things become murky.
Right.
And these are very
practical questions, but at the same time
we don’t foresee that even there will be
any controlled clinical trial to assess
the effect of these nutraceuticals or even
things that we take for granted on a daily
basis. So this is where, again, the N of
one experiment, self-experimentation of
yourself, trying different kinds of
behavior intervention where you switch
from water to flavored water and does it
make you feel different.
I mean it’s not only weight gain. One has
to assess sleep, activity,
feeling alert, feeling productive.
Maybe measuring your fasting
blood glucose levels.
Blood glucose level if you
have a continuous glucose monitoring
system.
Right, even better.
And so this is where
strongly this self-experimentation by
informed citizens who are very careful,
they’re not really…they don’t have any
adverse metabolic disease. And, again, I’m
not promoting that everyone should start
doing self-experimentation.
People are doing it.
But as least whatever
they’re seeing they should share.
Yeah, they could share it with
myCircadianClock.
Yeah. So even if they put
some notes in the feedback section,
then we’ll compile all of those, and then
that will help us to take informed
decision about animal experiments. At
least we can go back to animals and say,
“At least in animals we have tested this,
this is how it works.”
Right.
And in the future maybe
that will trigger some…
Or maybe you’ll get 10 people
to come back and say,
“Oh, I started drinking my,” you know,
“Diet Coke in my fasting window and all of
a sudden my blood glucose level started to
get worse.”
Yeah.
So you’ll have multiple people
telling you this. Well,
maybe there’s something to that.
Yeah, yeah.
But, you know, people are
asking about things, like even
supplements. And I think, like, you know,
again, you’ve answered that we don’t,
you know… You know, are you taking fish
oil? Is it a fatty acid?
I mean maybe… There’s lots of things
here because that is, you know…
So if you’re taking a fish oil supplement,
then what do you think?
That’s different than taking,
for example, vitamin D?
Well, it’s a question of…
I like to compare this to,
say, physical activity. Somebody is
completely sedentary. For that person
going for a walk, whether it’s in the
morning or evening or midnight doesn’t
matter because this person is getting some
benefit of physical activity.
Similarly, if somebody is very low on
vitamin D or needs that fish oil
supplement, then what time the person
takes doesn’t matter because that
deficiency is getting corrected.
Yeah, that’s true.
So that’s true. But then if
someone now dials it slightly higher and
says, “Well, you know, I want to have this
protein drinks that’s 25 grams of protein
after my exercise late at night. Is it
okay?” Then that’s where I’ll say,
“Well, then that’s going to affect your
gluconeogenesis and muscle recovery.
And maybe if you have done a very
strenuous exercise, if you’re training
for, like, Ironman or something like that,
yes, you have to have that to recovery.
Yeah. So that was actually a
question I think people were…
Someone was asking about weight training
at night, if that would counter.
If they, you know, eat late at night after
weight training, if that would counter.
And I think that’s kind of
pushing it a little bit.
Yeah, that’s
pushing a little bit.
Which is kind of
what you’re saying.
And, again, it depends on
your training schedule and other stuff,
what do you want to get the most out of
it. Like, for example,
if you’re used to training late at night
and having that protein and carb drink
right after that, what if you do a little
self-experimentation and move that to,
say, 5:00 or 6:00 and see whether it
actually helps you do one extra pushup or
to go for another five minutes, or is it
actually compromising your performance.
So, again, it’s very personal. And then
some of these very kind of athletes who
are pushing themselves to the limit, they
want to squeeze the last drop of
performance out of it. And for them I
think self-experimentation is the best way
because there is no way we as scientists,
we can do that kind of study in our labs
with a number of subjects who are as
competent as them, and then controlling
for everything. So it
would be very difficult.
But you did show in one of
your animal studies that a shorter feeding
window for these animals, like, for
example, nine hours…or it was eight or
nine hours.
Eight to nine,
both of them.
Endurance…
Endurance went up.
…performance went up. So you
do have some evidence of being able to
squeeze the last drop of performance
maybe.
Yeah. So that way you
clearly see endurance went up.
And the reason why we did that experiment
was we thought, “Well,
if the mice are feeling fasted for a long
time, will their athletic performance or
muscle performance go down?” Because our
worry was their performance,
athletic performance, might go down. And
in that way it might be harmful for some
people for whom physical activity is
needed. And, for example,
many shift workers, they need that
physical performance.
Right.
That’s why we did it.
And we realized that their
grip strength, which is similar to how
much weight a person can lift, that did
not change, that stayed the same.
But the endurance, being on the treadmill
for a long time, that actually
significantly increased, and
in some cases it doubles.
Doubles?
Yeah.
I’ve noticed this in myself.
I’ve done, like, an eight or nine-hour
eating, you know, schedule and the next
day… So if I’m fasting for a longer
period, the next day I go for a run in the
morning and my endurance is…
And this is, I mean, we’re talking like
five or six times, maybe seven times I’ve
noticed it.
Yeah, yeah.
I mean it’s a clear pattern.
Yeah.
My endurance is dramatically
improved. I mean it’s incredible,
like, I just can keep running. Like,
whereas usually I’m tired and I reach the
mark where I’m like, “Okay, this is it,
finally I’m getting”…
You know, you kind of sprint to the end
and now I just keep going.
Yeah. No, we see that.
There are many people who have given us
this feedback that their endurance does go
up. And then what is interesting is,
again, their endurance improves, and then
once in a while they say,
“Well, I can go back to 12 hours,” and
then immediately they see the reversal of
that endurance.
Right. It does, exactly. It
totally reverses, yeah.
Yeah.
You know, I know there’s been
some recent studies coming out in the last
year or so where exogenous ketone bodies
have been given to endurance athletes and
it improved their endurance capacity.
Which makes sense because endurance
heavily relies on mitochondria. Right? So,
I mean, it completely…
I mean if that’s actually part of the
mechanism with the time-restricted eating
in terms of a longer faster period one
would presume would have higher levels of
ketone bodies.
Yeah, we do see they have a
slightly higher level of ketone bodies.
So it makes sense.
Yeah.
Whereas… Well, I don’t know
what exactly you’re doing with the grip
strength, but, you know, it depends on
whether or not if you’re pushing them to a
high enough intensity where they’re
becoming glycolytic or not.
I don’t know.
Yeah. So, again, we don’t
know where the dynamic range of that
particular assay and we can’t ask
questions to mice. So this is where people
who are actually lifting weights are doing
something, a very different kind of
exercise. Endurance exercise versus
intense exercise, those are very
different. Maybe they can give us feedback
to see what happens.
Now in your study wasn’t there
improved lean muscle mass?
Yes, we did see lean muscle
mass improvement only on mice that were
given standard diet, not on high fat diet.
Okay.
The high fat
diet fed mice…
Yeah, I wouldn’t expect for
them. So they were given…so the mice
that were given the normal, sort of
healthier diet.
Yeah.
What was
their eating schedule?
They were
eight to nine hours.
So it was a shorter time
window they were eating?
Yeah, yeah yeah.
They had increased lean muscle
mass. Now is that something,
like, do you know why that is? Has that
been looked at?
We actually don’t
understand that, that’s another thing.
But we do see there is an increase in
PGC-1 expression in muscle,
so there might be an increase in
mitochondria function. But surprisingly in
the same mice we saw there is less
glycogen in muscle. And that’s kind of
counterintuitive. You might think that,
“Well, the muscles may be loaded with
glycogen, so that’s why their lean mass
went up.” But at the same time what we
think is maybe, because they have less
glycogen, we know that if the muscle has
less glycogen than after normal activity,
then glycogen may be completely depleted.
And when they eat, they have a much better
feeding response. So that means a much
better glycogen synthesis response. So
they may be making and breaking glycogen,
making and breaking triglyceride on a
daily basis, or protein on a daily basis.
So in that way I think they may be
maintaining much better muscle health.
Because they’re also going through some
gluconeogenesis, they’re breaking down
some protein. So maybe some of the
structural proteins that get modified and
maybe they get damaged, they’re kind of
getting cleansed, they’re getting cleaned
out of the system by this eating and
fasting rhythm. So, again,
it’s all speculation, so we have to go
back to the muscle samples.
Yeah. You have the data, you
just don’t know the mechanism.
We don’t know the
mechanism.
But people are very
interested. I mean increasing lean muscle
mass is hard to do and there’s a lot of
huge interest in it.
Yeah.
Huge interest.
No, actually we have been
seeing this reproducibly now in multiple
strains of mice. And it happens with a
balanced diet. So this is where the
nutrition quality does…
Play a role.
…play a role.
Which makes sense.
Yeah.
Yeah.
So we can’t expect people
to eat the same fatty food and expect lean
muscle mass.
Right, yeah. So there’s a
nutritional component to it in addition to
eating within a restricted time window.
Yeah.
Which completely makes sense.
Yeah.
Some of these other questions
that are just frequently asked.
You know, a lot of people just
really…they want to do time-restricted
eating and they want to do it right.
Yeah.
And so, you know, some of
these questions can be a little silly,
but it just shows how people are thinking.
Like, for example, does toothpaste start
the clock?
If they’re not swallowing.
So if you’re not swallowing
it, probably not starting the clock.
Yeah. Yeah. It’s not
starting, it’s actually resetting the
clock.
Resetting.
So I think we have to also
think of time-restricted feeding,
although we came from a circadian clock
lab. So that’s why we always get connected
with circadian with circadian clock. But
time-restricted eating has also feeding,
fasting, that whole physiology type to it.
So the other way to ask the question is,
“Does brushing your teeth or mouthwash
break the traditional definition of
fasting?” And definitely it’s not breaking
that, it’s not putting food in your
stomach so that the stomach will start
processing it and insulin starts going up
slightly and blood glucose going up. So in
that way we ought to keep in mind that
we’re bringing that definition back once
in a while. No, it does not break that
fast.
I think that’s a good way to
explain it. Some other people are…
We talked about the night shift work, and
so that was good. And you also mentioned
another thing people asking about is when
can you start a TRE schedule in a person’s
life, like developmentally.
Yeah.
Can you start as a toddler? Is
that too earlier?
I think, yeah, so we know
that in newborn the suprachiasmatic
nucleus is not even fully developed and it
may not be even fully connected to the
rest of the body. And that makes sense
because the babies are going through a
very rapid growth phase. And what they
need at that time is a lot of nutrition
and growth. So TRE may not be desirable at
that time, not at all.
In fact, since it can trigger adverse
effects, so I won’t recommend.
I think a rule of thumb is when babies or
toddlers begin to sleep eight to nine
hours continuously through a night anyway,
now their physiology or their sleep
pattern is already getting used to being
without food for seven to eight and maybe
nine hours. And that maybe a time when at
least one can begin the first term phase
of time-restricted eating. That is to
start with a schedule, a well-defined
morning breakfast time and the last meal,
or even bedtime. So recently there was a
study done in England saying that babies
were having a very regular scheduled
bedtime and also last meal, protected from
childhood obesity even five,
six, seven years down the road. So
although they did not measure when these
babies were eating and all that stuff,
what I think is having a regular bedtime
itself is a very strong timing cue that
these babies are going to bed at a certain
time and most babies will sleep for 8, 9,
even 10 hours. So they’re already into 10
hours of fasting just through their sleep.
And then it takes an hour for them to get
up and then get ready and then start
eating. Or for some babies they may finish
eating, and then they’re reading a book or
something and somebody is reading them a
storybook. So you’d add that one hour
between the last food and going to bed.
So in that way I think the rule of thumb
would be when babies start to sleep for
eight to nine hours continuously, then
that would be a good time to start putting
them to bed at a fixed time. And then the
next thing would be giving them breakfast
at the same time every day, or having the
last meal or the dinner time fixed.
So then their body gets used to it. And
then by the time they’re in Elementary
school it will be easy for them to adopt a
12 hours eating time,
and then if they want maybe they can go
down to 10 or 12. So that itself is a very
good limit on them. So in that way, I
think, it’s a very clear example that TRE
is something that you can start very early
on and it can be a lifelong habit.
Excellent. Excellent. Let’s
see what are the other really common ones.
Some people are kind of curious whether or
not there’s…if anyone has looked at or
even if you have any thoughts about within
your eating window,
like, does it matter if you’re having lots
of frequent meals or maybe two meals?
Yeah, so that’s a question
that comes up very frequently.
And, actually, this is where, again, I
kind of go back and forth between what we
know about metabolism and response to
eating. And we know every time we eat a
good amount of food, even a good size
snack, there is enough sugar in most of
the snack that it will trigger an insulin
response. Our blood glucose will go up,
it will stay up for maybe 90 minutes to a
couple of hours, and then it will come
down. So every time we eat we essentially
trigger our insulin to go up slightly,
so there is this anabolic hormone going up
and staying up for maybe one or two hours.
So in that way our body is getting into
that fat storing mode every time we eat.
So with that in mind I would say the
smaller number of meals within that eight
or nine hours is better than eating every
one hour within that eight to nine hours.
But, again, this is where we don’t have
hard data. It’s just going by my
prediction based on what we know from
physiology. And this is,
again, this might hold true for normal
healthy people who do not become
hypoglycemic after six, seven hours of
fasting.
Right.
But we know that there are
a lot of people who actually prefer to eat
twice. And this is something that we find
with many people who adopt TRE,
that what happens is after 14 to 16 hours
of fasting their hungry to have a good
breakfast. And if they have a good
breakfast with enough, say,
protein, fat, and some complex carb, then
naturally they’ll not feel hungry for
seven to eight hours easily.
Right.
And then they have another
dinner or maybe one snack in between.
And essentially that has even happened to
me. I eat mostly two meals,
my big breakfast, and then I go to dinner,
and it actually helps me stay productive
throughout the day. I don’t have to waste
that one hour for looking for food,
having lunch, and then the postprandial
dip. So the short answer is the less
number of meals may be better.
The same thing for me. It
depends on what I eat for breakfast,
and I’ve noticed change. Like, if I eat,
like, a breakfast that’s got higher
protein, higher fat, I’ll be satiated for
much longer.
Yeah.
As opposed to… Or even have
higher fiber.
Yeah.
As opposed to, for example, if
I eat yogurt and some berries.
Yeah.
Not good.
No, not good at all.
I will be hungry a couple of
hours later.
The same thing with me.
Yeah. So that’s definitely not
my go-to breakfast.
But I also wanted to mention, because you
were mentioning the,
you know, what we do know about metabolism
and how even, you know,
a small amount of food can trigger an
insulin response and, you know,
elevate blood glucose levels. Some people
might be thinking, “Well,
what if I just do, you know, like a
ketogenic, just fat only, just eating
fat?” And the reverse of that would be
also, I guess, you know,
if you think about metabolism, we know
that a high fat meal, you know,
if you’re going to use that fat as energy,
you have to…you know,
it has to be imported into the
mitochondria and it undergoes this process
called beta-oxidation, there’s
transporters, carnitine
palmitoyltransferases, CPT transporters.
Those also are regulated by,
guess what, fat.
Fat.
Malonyl-CoA inhibits it.
Yeah.
So you could eat that fat
meal, and then eat a smaller fat meal
later, and that second meal will probably
not be used as energy,
but stored as fat.
Yeah.
So that’s what happened.
Right.
And also another thing is
what we find, a lot of people it’s very
natural that some people think that a
particular diet is rich in protein,
that doesn’t mean that it’s only pure
protein. So one simple example is many
people think that lentils are high in
protein, so lentils…they can just eat
lentils and they’ll get a protein source.
But lentils are only up to 25% protein and
almost 70% carb. So when they eat lentils,
they’re actually eating a very nice
carb-rich and protein-rich diet and that
carb will trigger a good insulin response.
Right, yeah. Great. Let’s see
what other ones that are really frequently
asked. We talked about xenobiotics,
obviously pharmaceuticals.
If your doctors tells you to take a
pharmaceuticals at night, then…
Yeah, then you have to take
it at night.
Yeah.
And your doctor overrides
any other thing that you are
self-experimenting.
And as we were talking about a
little bit earlier off camera,
xenobiotics themselves are
on a circadian clock.
Yeah, xenobiotic metabolism
is strongly circadian.
And there are three or four meso
xenobiotic degrading enzymes.
So actually these are the transcription
factors that control many of the
cytochrome P450s that break down
xenobiotics. And these are strongly
circadian. And, in fact, a lot of the
circadian rhythm research we use one of
the xenobiotic regulators as a reporter,
as a marker. Because even the circadian
clock components are not as robust as the
xenobiotic metabolizing transcription
factors and enzymes, so that’s why. In
terms of xenobiotics, almost every type of
xenobiotic absorption, metabolism,
excretion is strongly circadian regulated.
And that’s an amazing area, a new area of
circadian rhythm research.
So that is what time of the day a
medication may be better absorbed and
better…most effective. Because any
medication that we take is actually going
and interacting with a protein, in most
cases. It’s going and inhibiting or
stopping a protein or activating that
protein. What if that protein is actually
not there? Then we are essentially taking
a drug with no benefit when the protein
turns off. So, for example, we take the
medication in the morning,
but the protein actually comes to play in
the evening. So then this medication has
no impact, and then the doctor will keep
on increasing the dosage so that it comes
to a point where there is some medication
that’s remaining at the end of the day
that will start to have
its intended effect.
Wow.
But then the side effects,
the adverse side effects will go up with
the increased dosing. So that’s why there
is now interesting…there is a lot of
interest on what time of the day a given
drug target reaches its peak,
and can we match drug timing with its
target so that we can have the same effect
with less of the drug so that we can
reduce adverse side effects and we can
increase efficacy. So that’s a whole new
area of research that’s going on.
And the small or the most impactful
statement about that is recently people
have found that nearly 70% of FDA-approved
drugs have their targets cycling in the
body. So that means for 70% of FDA-drugs
just timing can make it a drug or make it
a poison.
Wow.
So that will be an amazing
area of research in circadian rhythm.
Yeah. I mean personally I’m
very interested in this field not…
I mean I think it’s very important for
that reason, really because so many people
are taking pharmaceuticals. But I don’t
personally take pharmaceuticals,
but I do take things like turmeric.
Yeah.
Curcumin.
Yeah.
You know, these polyphenols,
which are xenobiotics.
And I’m interested in can I take my
curcumin at a certain time of day and it’s
more effective, I get more bang for my
buck. You know, because it’s metabolized
quickly, so I would like to find, you
know, that time window. That would be kind
of cool. So, okay. I think we covered the
questions that are pretty frequently
asked. Yeah, great. So, again,
this…getting back to the
myCircadianClock I think is sort of key
because you’re aggregating data from all
over the world, right?
Yeah.
You have people now from…
So we have people from
almost every continent, except Antarctica.
That would be cool.
If somebody is going to
Antarctica and really if you are…
You need to get some of the
researchers that are on the station over
there, the research station.
And we haven’t hit the
International Space Station yet.
Okay. That would be cool too.
That would be cool because,
you know, in ISS they are going through a
90-minute day-night cycle because the
space station makes one revolution around
the Earth every 90 minutes. So they see a
sunrise and sunset every 90 minutes.
Wow.
And actually they’re the
ultimate shift workers.
Right.
And we know that they
struggle with it a lot and recently the
ISS is fitted with circadian lighting, so
they will go through a simulation of
light-dark cycle. Not a light-dark cycle,
but blue light increased and red light
increased, that kind of cycle. So we’ll
see how it improves their life.
Yeah. That’s really cool. For
the data that you’re aggregating…
I guess aside from people putting
comments, which are probably extremely
useful. You’re learning, obviously, things
like the IBS and all these things you’re
learning from people putting their
comments. Is there any mode of tracking,
like, cognitive function of mental
function, or is it just the comments that
you’re [Inaudible]?
Yeah, so we haven’t done
anything… Actually, we are going to
release a newer version of the app based
on many comments that we received so it
will be a little bit more user-friendly,
hopefully. And, yeah,
so if we add more functionality to the
app, then it becomes more complicated for
a lot of people.
Yeah.
So that’s why we have to
find that balance where we have to kind of
stop and then see the right balance. Or
maybe bring up some cognitive functions,
or link them, link our app to other apps
that do cognitive function.
I’m just… I’m personally
curious in whether or not time-restricted
eating affects cognitive function, mental
performance, and also just brain aging in
general. You know, because we do know that
shift workers, for example shift workers
that have worked like 10 years or more,
have, like, their brain’s age at,
like, an accelerated rate. Their brains
look, like, six and half years older than
age match controls or something.
Yeah.
And I think there’s some
animal studies showing if you make mice
eat when they’re not supposed to eat, so
when they’re usually sleeping,
so for them during the day, I think
they’re, like, hippocampal function was,
like, messed up or long-term potentiation
was messed up in learning memories.
Yeah, so there are many
studies done. For example,
in high fat diet fed mice a lot of
cognitive functions and social functions
have been assessed. And we know a high fat
diet disrupts our circadian clock,
they eat randomly. So in that way we know
that there is already a deficit that is
already a problem with brain function. And
now they will…those kind of experiments
will guide us to see if we give the same
high fat diet within eight hours or nine
hours to mice and we do the same assays,
what will happen, whether we’ll see
improvement and benefit. So that’s one set
of experiments. The other set of
experiments that will be very useful…
And I’m sure somebody else must be doing
it because if I can think of an
experiment, somebody else is already doing
it. That’s to take all these animal models
of Parkinson’s disease or Alzheimer’s
disease, and then put them on
time-restricted feeding.
Yeah, it seems obvious.
And then see whether the
performance improves.
Yeah.
You know, I’ll not be
surprised if we see these kind of studies
coming out in the next six
months or a year.
Well, surely, I mean, if
you’re clearing away, at the very least
clearing away some of these protein
aggregates because you’re having a
constant fasting period, then if, indeed,
those protein aggregates are affecting
cognitive function, you would imagine that
that would be improvement.
And also what we know from
sleep research over the last three,
four years, one of the big things that
came out from sleep studies in the last
few years is we knew sleep improves
learning and memory, synaptic plasticity,
etc. But now we are learning that sleep
actually improves cleansing the brain.
So, for example, the xenobiotics and other
stuff, the gunk in the brain gets broken
down and is cleaned during this sleep
time. And I would say that there might be
some aspect of fasting because, of course,
in all these studies the animals were
eating less when they sleep. And so then
the question is, “How much of fasting
contributed to cleansing the brain?”
You’re talking about the
glymphatic system being activated.
The glymphatic system.
That would be super
interesting.
Yeah.
That would be very
interesting.
So that’s also another
reason why we think that,
well, maybe fasting is actually improving
sleep by affecting maybe the xenobiotic
metabolism or something else. So it’s kind
of interesting that we did a very simple
experiment a few years ago and now we have
more questions than answers.
And this is exciting.
Yes. Do you have any
neurobiologists in your lab that would be
interested?
Yeah. So we are
collaborating with experts in this field
who work on neurodegenerative disease to
see what is the impact of time-restricted
feeding on these mouse models. And, of
course, we cannot just take one mouse
model, we have to use a multiple number of
mouse models to make sure that this
is…at least in mice, we can assess where
there are benefits or adverse effects on
multiple strains. And then we can come to
human studies.
Yeah. I know the glymphatic
system is, like, one of the major ways the
brain clears amyloid beta plaques. Like
you said, among other gunk and things.
Yeah.
That’s part of the gunk.
Yeah.
So that would be extremely
interesting to see if your eating schedule
also affected that, as well. Definitely no
shortage of interesting things to ask.
No, no.
So you’ve got a website?
Yes. I have a website
called mycircadianclock.org.
And that website has a lot of information
as blogs. And also in the first phase in
the informed consent what we do, we ask
people to go through the informed consent
to see what they are asked to do or what
they may volunteer to do as part of the
study. They may give us some information
about themselves. And in that way we can
relate. As we increase the number of fans,
we have more participants.
We’ll always have some participants who
belong to a certain age group,
gender, or socioeconomic condition, so
demographic. So in that way we can always
figure out what is their existing
lifestyle and what they tend to change,
what they can change. And then after the
sign-up they get the copy of the informed
consent in their e-mail. So it’s very
important that you give an e-mail address
that actually works, we are not going to
use the e-mail for anything else.
And we are actually overseen by a
committee of ethics, ethics committee,
who reviews everything that we do. Any
data that we, even in the future,
if we want to share, it has to go through
that ethics committee,
it cannot be given to any entity for
profit. And so in that way we maintain
privacy very strongly. And then once they
download the app and start collecting,
one interesting thing is what we find.
People hear about our study through
podcasts or other things and they start
doing time-restricted eating from the
get-go. So in that way you don’t get a
picture or snapshot of what is their
lifestyle before they adopted
time-restricted eating. So one request is
for the first one or two weeks it’s better
if they just continue their current
lifestyle. Even if they were eating in the
middle of the night once in a while,
it’s better to have that in the record so
then we can say, “This was”…then people
can themselves compare, “This was my
lifestyle before.” And then after two
weeks when they set their new goal, or if
they say, “Well, I can’t do only 10 hours
of eating,” that’s fine. But 12 hours, or
even 8 hours. Then we can compare how was
life before TRE and how is life after TRE,
and we can compare those two.
And what happens is, yes, we ask to log a
lot of different things.
Some people do it and some people may not
like to do it, but that’s okay.
If people can log at least one thing,
whether it’s sleep, whether it’s food,
then that’s much better than not logging
at all. And then another thing that we
notice is some people will get into the
habit of time-restricted eating for four
to six weeks, and then they stop
recording. And we know that they
actually…they say, “Okay, I don’t need
this guidance,” or, “I don’t need to log
this data, I can do it by myself.” And
that’s fine. But for us it will be really
nice if they can log at least the first
and last meal for up to 12 weeks.
Because all of these will help us to
figure out whether you’re actually falling
off the wagon or you got it so that you
don’t have to do it for 12 weeks.
So in the next version of the app, when we
go to our ethics committee and ask
permission, we’ll say, “Well, you know, we
are finding that people get used to it in
six weeks. We don’t have to ask them to
monitor everything for 12 weeks.” So all
these things matter. And then once in a
while giving us some feedback.
If you see some improvement, please it
share with us. If you see any adverse
impact, that’s much more important, please
share it with us. Because then we’ll know
what are the adverse impacts and we can
report that to our committee and also we
can go back to mice and then see why this
happened. And that at the end of 12 weeks,
if people can record, say, their body
weight or any other measures that they can
record, then that will also help us. That
will help us to go back to mice or even
include in our final publications. Because
what we are foreseeing is we might begin
to start publishing from the app from the
end of this year onwards.
And there are many different ways one can
dissect the data, so there are many
different ways we can publish it. So the
more information we have,
what happened in response to TRE, the
better it is. And maybe we’ll go back and
then have re-contact with some of the
participants and ask them after one year
or after two years or after three years,
with permission from our ethics committee,
“Can you tell us are you sticking with
this habit? Or what actually made you not
to stick with the habit?” Because those
things are also important.
What are the other lifestyle factors that
are preventing us to stick to an eating
schedule? So we want to learn from people.
And we have to kind of learn it the other
way around. Instead of doing controlled
clinical trials and taking it to people,
we want to get from people’s experience,
and then see what sticks,
what doesn’t stick, and then
go back to basic science.
Right.
What you’re doing is fantastic.
Basic to bedside, and then
back to basic.
Yeah. You’re getting ideas. I
mean you’re thinking about things you
wouldn’t have even known to think about.
Yeah.
Because, you know, getting new
data and it’s fantastic.
So I definitely encourage
people to try this out.
Yeah. One of the already
published results that came from people’s
feedback is when we did the small
time-restricted eating study,
there were only eight participants. But
all eight of them said they slept better,
and we had never asked the mice whether
they slept better.
Right.
So we went back to our
Drosophila flies and we saw that they were
sleeping better. And then we went back and
looked at their brain transcriptome to see
why they’re sleeping better. So this is
one example where we went from a feedback
to doing a basic science research in flies
and actually publishing that data in
science, and then moving on to do more
molecular studies.
Yeah. So maybe that will
affect the glymphatic system if the eating
does make you sleep better.
Yeah.
Right?
[Inaudible].
And so you’re also on Twitter.
Yeah.
And your Twitter handle is…
SatchinPanda.
@SatchinPanda.
@SatchinPanda.
And anywhere else?
Got your website and Twitter.
Yeah, website and Twitter,
and then I’ll start maybe Instagram or
something.
All right. Well, let me know.
Yeah.
Thank you so much, Satchin.
Thank you.
Always a pleasure
to talk with you.
Thank you so much. Because
you are doing the right thing for science.
It’s communicating science to the masses,
this is what we scientists cannot do and
we need people like you. Thank you.
[Inaudible], Satchin.
Thank you.