[Rhonda]: I guess, also, what I was wondering is if you think about it, like, so the minute
you start your metabolism clocks in your liver, for example...
[Satchin]: Yeah.
[Rhonda]: ...the minute you start those metabolism clocks by your first sip of coffee and breakfast,
the clock's ticking and you're insulin-sensitive.
You're gonna be able to, you know, take glucose up into various cells after you eat.
And then once you get past that time, so you're now 12 hours out, you're not gonna be as insulin-sensitive.
So, let's take someone that is doing intermittent fasting, and they wake up at 6:00 or 7 a.m.
They have coffee and breakfast, a big breakfast, and they're done.
So then they fast for 12 hours, so now it's 7 p.m., maybe 13 hours, 7:30, 8 p.m.
They've been fasting all day, so they're getting a lot of the activation of some of these...
[Satchin]: Yeah.
[Rhonda]: ...you know, stress-response pathways like AMP kinase and, you know, they're making
some ketone bodies, Kreb, all these similar pathways are being activated.
[Satchin]: Yeah.
[Rhonda]: ...that, you know, time-restricting feeding also activates.
But then, they take a big meal at 7:30 or 8 p.m., so 12 or 13 hours after they've already
set their clock.
[Satchin]: Yeah.
[Rhonda]: So now in theory, then, they're…well, I don't know if this is true or not, maybe
the intermittent fasting changes some of this, but, you know, their liver wouldn't be, you
know, it wouldn't be working as well at that point.
Or do you think that just because they were fasting all day that may change some of that
and allow them to then eat this meal and it wouldn't have such a negative effect?
[Satchin]: Yes, so that's a very interesting question that we get many times and we are
thinking of addressing that.
It's very hard to do that in experimental animal models because if you fast them, if
you give them two meals, they reduce their caloric intake, but it's possible to do.
But here is something that came out only in last three to four weeks.
You mentioned early in our conversation that insulin sensitivity is not the same at the
end of the day, and the question is, if you fast enough during the day, is your insulin
sensitivity as good enough as in the morning?
[Rhonda]: Right.
[Stachin]: Then everything you can equalize is at least insulin, which is a big thing
in metabolism [inaudible 00:55:42].
So recently, what we are finding is actually the smoking gun came almost 10 years ago when
people who are doing GWAS studies to find whether there are mutations in given genes
that make us more diabetic or obese, surprisingly, people thought that, "Okay, so we'll find
some genes that regulate metabolism."
Right?
So that is the common sense.
But then the big surprise was they found melatonin receptor as one of their top hits.
[Rhonda]: Wow.
[Satchin]: And some of the clock genes, like cryptochromes, in the top five or ten genes.
That is not only in one study.
In multiple studies, they found it.
So there are the smoking gun.
What is melatonin doing with this obesity and diabetes?
And recently, what is interesting is people are finding that melatonin receptor is present
in pancreatic islet cells, beta cells, and melatonin receptors, when it's engaged with
melatonin, it signals and it inhibits insulin secretion.
[Rhonda]: What?
Really?
[Satchin]: Yeah.
So it just came out, like, four, five weeks...
[Rhonda]: Wait, so you know that I've always wondered, because, like, most of the melatonin
in the body is actually made in the gut, right?
So tryptophan from dietary protein gets converted into serotonin...
[Satchin]: Serotonin.
[Rhonda]: ...and that's converted in melatonin.
This is happening in the gut and...
[Satchin]: No, serotonin goes to pineal and then gets into...
[Rhonda]: So there's, so this, so the, it happens in the gut and it also happens in
the brain?
[Satchin]: Yeah.
[Rhonda]: There's two separate genes that do this.
[Satchin]: Yeah.
[Rhonda]: And what's really interesting is I don't know what melatonin...why are we making
it in our gut?
So I'm wondering if it's somehow signaling to the pancreas.
[Satchin]: Yeah, so this is completely new.
So that's why now it brings up...now, it helps us to connect this dot that people have.
I mean, for the last 35 years clinicians know that the insulin sensitivity is very different
between day and night.
And then the GWAS, the human genetics people came and said, "Yes, there is some smoking
gun with melatonin."
And now, finally we are finally saying, "Yes, melatonin receptor can actually inhibit insulin
secretion."
So in that way, having an evening meal, maybe with candle light dinner, is not a good idea
because you have less light, so you have more melatonin, and that can inhibit... [laughs]
[Rhonda]: That's fascinating.
I have to get that study.
It's very, very interesting.
[Satchin]: So that's one case where we might think that late night, even if you control
food calorie, the same calorie taken in late in the night versus early in the evening might
have different effect.
In fact, there was one study that came out from Spain, two or three years ago now, showing
that in a weight loss trial they actually found...although everybody got the same diet,
they were controlled for activity, clearly there were two groups of people.
One group lost weight significantly, a lot of weight loss, and the other group lost moderate
amount of weight.
And when they did post-hoc analysis to see what is the difference, the only difference
they found was the group that lost weight, they actually had their lunch…in Spain,
people eat lunch at 3:00.
So they ate lunch earlier whereas the group that did not lose weight, two months, they
ate their lunch later.
So that is another piece in the puzzle saying that late-night eating might actually prevent
weight loss.
[Rhonda]: Right.
And you've now translated some of these findings into some human trials using this smartphone
app that you've developed.
So that's kind of neat as well.
[Satchin]: Yeah.
So one thing was we wanted to see is when people actually eat.
And in typical nutrition studies, people are asked, "When do you eat lunch, breakfast,
and dinner?"
But that doesn't capture, really, all snacking and everything.
So that's why we thought how to capture when people eat in a very evidence-based manner.
And we thought if we asked people to take a picture of their food, then the picture
will speak a volume.
It will have every single component.
They would not have time to describe everything on their plate, but we'll capture that.
It will also have the timestamp.
So the whole idea was to see when do actually people eat.
Are there a lot of people who eat like mice do that nibble throughout the day and night?
And if they actually eat until, say for more than 12 hours or 13 hours, then they are the
ones who may benefit from time-restricted feeding.
So when we did this experiment, when we started this project, we thought that…everybody
we asked, they would say, "Yeah, I wake up, I have my first sip of coffee and usually
I eat all of my food within 12 hours."
So we were very discouraged to hear that.
But then we carefully selected people who don't do a shift work so they will not have
to work in the nighttime, that's when they're changing their eating time, and they're also
not on any medication that will change their hunger or satiety.
So we took really healthy people from San Diego area because we live here, and they
just had to take a picture of their food.
And that way, it was also less stressful for them to enter what they ate, and portion size,
etc.
[Rhonda]: Way better compliance, I'm sure.
[Satchin]: Yeah.
There's only three clicks, because if you think about it, open the app, take a picture,
and then press the save button.
And the optional was they could actually describe what they ate.
But we found very few people actually describe what they eat.
So that means just typing that on your left hand when you're eating is not a very pleasant
experience.
What we found is out of these 156 people, nearly 50% people eat during 15 hours.
So that means between their first bite, non-water bite, to the last non-water bite or sip in
a given day is around 15 hours, which some people think, "Oh, that's normal because if
they start their first sip of coffee at 6:00 in the morning, and then after dinner they're
watching their favorite show, and then had another glass of wine or chips, that can go
up to 9 p.m."
But then we asked...well, in mice, we can actually take away food and enforce time-restricted
feeding.
We can't do that with humans.
They have to be self-motivated.
So we asked whether it's feasible for some people to at least restrict the time.
So we asked eight of them to see…they were eating for 14 hours or longer and they were
a little bit overweight, so we asked if they can eat within 10 to 11 hours.
And we said, "We are not going to ask you to change what and how much you eat.
The only thing you have to do is select your own time, depending on what time you go to
work or what time you come back, select your own time until we'll have 10 to 11 hours and
try to stick to it every day, even on the weekend."
And surprisingly, all of these eight people, they self-selected their 10 hours, 10 to 11
hours, and they stuck to it for 16 weeks, and at the end of 16 weeks they came back.
We saw that they had lost around 4%, 3.8% body weight within the 16 weeks.
They didn't have to do too many, they didn't have to read labels, they didn't have to type
portion size.
But then when we asked them, "Why did you do it," what is surprising is they said they
slept better and they felt more energetic in the morning, and that's why they did it.
And since they didn't have to count calories, it was also good.
But what is surprising is in mice, if you do the same experiment, mice will chow down.
They will eat the same number of calories as when they have free access to food.
But in humans, these people in our study, they actually ate 20% less calories.
Even though we asked them to reduce their time, they ultimately reduced their calorie.
But if you think about it, this is a much better way to control, manage their diet than
to count calories.
So in some way this study is inconclusive to say whether time restriction alone was
beneficial for weight loss.
But what it showed is the feasibility that some people can time-restrict and that can
be an indirect way to reduce your calorie.
And since we're collecting picture of every single food, we can also ask another very
simple question.
"What is the time of the day when people are more likely to eat certain type of food?"
As you can imagine, we found people drink most of their coffees, 70% of their coffee,
within four to five hour's interval in the morning.
And people ate 70% of their alcohol in the evening, four to five hours.
So now imagine if somebody's time restricting to the daytime, then he or she is more likely
to lose on alcohol.
So in that way, that also improves the quality of diet.
So since we humans eat different type of food at different time of the day, depending on
which interval we choose may indirectly result in change in nutrition quality, and to some
extent, quantity.