How Fasting & Caloric Restriction Impact Health | Dr. Satchin Panda & Dr. Andrew Huberman

Summary

The video discusses a study exploring whether the longevity benefits of caloric restriction are due to reduced calories or timed feeding. Mice on a calorically restricted diet lived 10% longer than controls. However, mice on the same calorically restricted diet timed to their active period lived 20% longer, and mice timed to their normal feeding period lived 35% longer. This suggests the timing of food intake, not just caloric reduction, impacts longevity. In humans though, a small difference in feeding window timing did not impact weight loss. More research is needed, but time-restricted feeding may provide longevity benefits beyond just caloric restriction.

Takeaways

• 😀 Calorie restriction extends lifespan in rodents, but it was unclear if this was due to reduced calories or changes in feeding timing
• 😲 Restricting feeding to only the active cycle extends lifespan even more than continuous calorie restriction
• 🚨 Feeding rodents only during their normal fasting period (equivalent to humans eating only at night) had the biggest impact on longevity - up to 35% longer lifespan
• 🤔 None of the known biomarkers of longevity predicted differences between the feeding regimens
• 🧐 This suggests there are biomarkers linked to timing of feeding and longevity that are still unknown
• 😕 In human studies, time restricted feeding within already habitual 10-12 hour feeding window showed no additional weight loss benefit
• 👍 But this was only a 2 hour daily difference, much less than tests in rodents which vary timing more extremely
• 🤝 When calorie restriction is done within a 12 hour or less window, the precise duration does not change longevity benefit in rodents
• 😉 Interpretations of this human study's results in popular media were often misleading about value of time restricted feeding
• 📝 More research is still needed in humans on potential longevity benefits from changes in feeding timing, not just calorie reduction

Q & A

What was the key finding from Joe Takahashi's 2017 study?

Joe Takahashi's 2017 study showed that most caloric restriction protocols actually create a condition of time-restricted feeding, where mice eat their full daily allotment of food within 2-4 hours.

What methods did Joe Takahashi use in his follow-up study to precisely control mouse feeding?

Joe Takahashi worked with engineers to develop a smart cage that could program how much food is provided to mice at specific times, allowing precise control over caloric intake and feeding/fasting duration.

How much longer did calorie-restricted mice live compared to ad libitum fed mice in Joe Takahashi's study?

Calorie-restricted mice that ate small frequent meals lived 10% longer than ad libitum fed mice. Calorie-restricted mice that ate within a 12 hour window lived 20% longer. And calorie-restricted mice that ate only during their active/nighttime cycle lived 35% longer.

What impact would a 35% increase in lifespan potentially have for humans?

A 35% increase relative to an average human lifespan of around 80 years would equate to an additional 25-35 years of life.

Did known biomarkers of longevity predict differences between calorie-restricted feeding groups in Joe Takahashi's mouse study?

No, known biomarkers like A1c, cholesterol etc. did not predict differences in longevity between the calorie-restricted mouse groups in Joe Takahashi's study.

What were the feeding windows used in the human time-restricted feeding study discussed?

Participants habitually ate in a 10 hour window. One group did 25% CR in a 10 hour window. The intervention group did 25% CR restricted to an 8 hour window.

Why did the human study likely show no additional weight loss from time restriction?

The human study compared 10 vs 8 hour feeding windows. Prior mouse research shows no major differences within 12 hour windows, so a small 2 hour reduction likely wasn't enough to further impact weight.

What appears most important for achieving benefits of caloric restriction in mice?

Consuming a sub-maintenance calorie level appears most important. The exact duration of feeding window doesn't change weight or longevity biomarkers as long as it's under 12 hours.

Might time-restricted feeding provide benefits for humans beyond just weight loss?

Yes, time-restricted feeding may provide various health benefits for humans distinct from and in addition to potential impacts on weight loss.

Would humans likely see 35% lifespan extension from time-restricted feeding as the mice did?

It's not clear. More research is needed, but even a fraction of that potential increase would be profound.

Outlines

00:00

😃 Famous mouse experiment showing time-restricted feeding extends lifespan more than calorie restriction

Describes a recent mouse experiment by Joe Takahashi showing that time-restricted feeding, where mice eat the same sub-maintenance calories within a 4 hour window, extends lifespan by 35% compared to 10% for calorie restriction alone distributed throughout the day. This suggests timing of food intake matters for longevity beyond just total calorie reduction.

05:03

😕 Popular media misinterpreting recent human time-restricted feeding study

Discusses a recent human study on time-restricted feeding where participants already ate within a 10 hour window. Reducing the window by 2 hours in addition to 25% calorie restriction showed no additional weight loss benefit. The limited difference likely explains the lack of effect, rather than implying no benefit for time-restricted feeding.

10:04

🤔 Mouse studies show no difference in weight loss between varied time-restricted feeding windows with calorie restriction

Notes other mouse experiments by Joe Takahashi where calorie restriction within varied time-restricted feeding windows from 2-12 hours showed no differences in weight loss or other biomarkers. Only longevity benefit required night-time feeding matching circadian rhythm.

Keywords

💡caloric restriction

Reducing calorie intake by a certain percentage (e.g. 20-30%) while maintaining nutrient levels. Shown to extend lifespan in animal studies. The video discusses whether the benefits are due to lower calories or time-restricted feeding resulting from how the restricted calories are provided.

💡time-restricted feeding

Limiting food intake to certain hours of the day, creating defined 'feeding' and 'fasting' periods. The video examines if this plays a role in the lifespan extension seen in calorie restricted animals beyond just the calorie reduction.

💡lifespan

How long something lives. Animal studies measure this to evaluate interventions like caloric restriction. The video describes experiments that tried to tease out if caloric restriction extends lifespan simply due to lower calories or due to the resulting time-restricted feeding.

💡biomarkers

Biological markers that can be objectively measured and indicate normal or pathogenic processes. The video discusses that known biomarkers did not predict lifespan extension differences between caloric restricted groups in the mouse experiments.

💡longevity

Length of life span. Used interchangeably with lifespan in the video when discussing the mouse experiments on caloric restriction and time-restricted feeding.

💡ad libitum

Latin term meaning 'at one's pleasure'. Used to describe feeding where animals have unlimited access to food, compared to restricted/scheduled feeding in the experiments.

💡cohort

A group of subjects with shared characteristics. The video describes using separate mouse cohorts for measurements requiring sacrifice so longevity could still be tracked in the main group.

💡mortality

Death rate. Mouse studies measure survival and mortality to determine lifespan extension from interventions like caloric restriction.

💡half-life

Time for 50% of a population to die/perish. Used as measure of lifespan in mouse studies because less sensitive to outlier long-lived mice skewing results.

💡chow

Food given to laboratory animals. Amount and timing manipulated in mouse experiments described to parse beneficial effects of caloric restriction.

Highlights

Caloric restriction extends lifespan by 10% in mice

Intermittent fasting may have health benefits beyond weight loss

Time-restricted feeding extends lifespan 20% beyond caloric restriction alone in mice

Timing of calorie intake matters for longevity, not just total calories

Nighttime restricted feeding extends lifespan 35% in mice

Equivalent to 25-35 more years of lifespan in humans based on mouse data

Known biomarkers did not predict longevity benefits in calorie restricted mice

Undiscovered biomarkers may relate to longevity

No difference in body weight/composition across restricted feeding groups in mice

Human study compared 10 hour feeding window to 8 hour window with caloric restriction

Just 2 hour daily difference in feeding window duration in human study

In mice, 2 to 12 hour feeding window with caloric restriction showed no longevity difference

12 hour feeding window optimal for longevity benefits with caloric restriction in mice

Popular press interpreted human fasting study results incorrectly

Time-restricted feeding simplifies portion control for some people

Transcripts

So there's a famous experiment

that was published last year by Joe Takahashi's lab,

and it came out in Science,

and that relates to caloric restriction.

And we kind of started with this idea,

we started discussing that the rat experiments were done

with caloric restriction,

and researchers gave reduced calorie conjunction

by 20% or 30%, and get that food,

the rats, and then subsequently mice.

And they all lived longer.

What is interesting is,

in all those experiments, the researchers came

and gave this bolus of food at one time,

whereas the ad libitum fed mice, or rats,

they had access to food all the time.

So they're eating all the time.

And then these rats were given 20% less.

And what happens is these mice, or rats,

they're not going to take that less food,

which is less than now,

and just eat a little bit of lunch

and then snack after three hours or snack after three hours,

they gobble up all that food within two to three hours,

maximum four hours.

Food is gone.

So they're sort of on the OMAD diet.

The one meal a day.

Yeah.

They're almost like in one meal a day,

three to four hours, food is gone.

Or you can sit there on four-hours eating or feeding

and 20 hours fasting.

So then the question became, well,

the benefit of caloric restriction as we know,

is it due to reduced calorie

or time-restricted feeding, or timing?

There is a timing component to it,

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

and then there is a long fasting.

And this is a difficult question to answer

because now you have to ask these poor grad students

or technicians to come and split that food

into 8 or 10 or 15 different small portions

and then give them to mice in every two hours.

So Joe Takahashi,

who actually published the first paper in 2017

showing that most caloric restriction study,

I mean he used the protocol

that was used by caloric restriction field.

It actually creates a condition of time-restriction.

So he showed that and then he went back

and worked with engineers to come up with a smart case

where he could actually tell,

he could program how much food is given to mice

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

So then he took this, for example,

supposed say the ad libitum fed mice

eats five grams of chow in a day.

And if you want to reduce calories by 20%,

then the CR mouse should get four grams of food,

and he divided this into 9 or 10 meals,

and then gave them in every 90 minutes.

So, in this case, they're eating small meals

throughout day and night, so there is no fasting.

So he can say that, well,

this mouse actually is not getting into fasting

because in every few hours is getting some food.

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

And he counted mice,

this is a very standard protocol,

people count how many mice are dying on which day

and then examine them to see whether they died

because there was an accident or there was a natural cause.

And then they calculate at the end

what is the half-life.

So, 50% survival,

because that's, on an average, that's a good indicator

because if there is an outlier

that will live for a long time, then that can skew.

So what was interesting was the ad libitum fed mice,

of course they lived certain number of days

and then this caloric restricted mice

that never got into super fasting,

but kind of eating, snacking throughout day and night,

they also lived 10% extra, 10% longer.

So that means caloric restriction extended lifespan by 10%.

I've wondered about this because recently, you know,

there were a bunch of news headlines

about intermittent fasting, and frankly I was frustrated.

If you looked at one major news outlet,

they would say time-restricted feeding

affords no additional benefit

beyond caloric restriction for weight loss.

SATCHIN: Yeah.

Then another popular press venue, let's call it that,

same study, described as

time-restricted feeding doesn't work.

Yeah. [chuckles]

Right, and then another one, it may be someplace

even more extreme, you know,

time-restricted feeding only beneficial

because of caloric restriction, or something like that.

So what you've essentially got

are three different interpretations of the same data,

all of which are, well,

two of which are true, one of which is false, in my opinion.

But, what I think people take away from that is,

"Oh, time-restricted feeding isn't valuable,"

which is not the case.

I think for many people it's a convenient way to eat

because, at least for people like me,

it's simpler to designate between portions of my day

when I'm eating and portions of my day when I'm not eating,

as opposed to portion control.

For other people, portion control can work,

but all of that is related to either maintenance

or loss of weight.

None of it deals with the potential health benefits

independent of weight loss.

Yeah.

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

obviously in humans it's hard to know

if a given treatment or experiment is extending life

because you don't really know how long

people would live anyway.

Right, whereas with mice, you have some sense

of when the mortality was likely to occur.

So, what can we say about time-restricted feeding

and longevity in terms of biomarkers

or in terms of any other indication

that people who start and stop their feeding window

at a consistent time somewhere between 8 and 12 hours

per 24-hour cycle

are tilting the scales towards living longer

as opposed to living shorter.

This example of this news article

that you mentioned is really interesting

because that relates to Joe Takahashi's study,

because I described that if you split calories

and eat throughout the day, throughout day and night,

then the mice lived 10% extra.

But if you now give mouse the same caloric restricted diet

and fit them during daytime,

whether within 12 hours or 2 hours,

then the mice live 10% extra

Beyond that.

Yes. So 20%.

20%.

So, okay, so let me make sure I understand

so that I make sure I understand.

If you take a certain number of calories

and you distribute them throughout the 24-hour cycle,

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

If you however restrict that to the active cycle,

so for humans, the daytime,

then they live 20% longer.

20% longer.

So, it's not just total caloric intake.

Yeah.

Meaning it's not just important

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

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

you eat those calories.

Do I have that right?

So now, still, the story is not over

because these mice are fed during daytime

when they're not supposed to eat.

That's right.

So for us it would be the equivalent

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

but a sub-maintenance calorie diet, I guess,

is the right way to say it.

But when he fed mice during nighttime,

when they're supposed to eat,

and they're getting the same number of calories

within 12 hours or 2 hours,

then the mice lived 35% longer than they control.

35% longer.

So ,scale to human lifespan, which we don't know,

but 35% longer would mean that,

and again, no one knows,

but humans, now, what is the average mortality

in the United States?

Somewhere around 80?

Yeah, so it's around 80, it used to be 80.

Now reduced a little bit because of COVID,

but let's take 80.

Okay, so people are then now living

somewhere between 25 and 35 years longer.

I'm putting some error bars on there.

Yeah, yeah, yeah. ANDREW: Amazing.

So that was really profound.

But now, you pointed out biomarker and other stuff,

so now if you look at any given time within that experiment,

and actually Joe went back

and had a separate cohort of mice, very similar,

and so that he could take tissue samples

and of course in this case you have to sacrifice the mouse.

And he looked for,

he did a lot of molecular analysis with known markers.

For example, hemoglobin A1C equivalent

or glucose control, cholesterol, all this stuff.

He could not find anything that predicted the benefit

of caloric restriction.

So that means in this experiment, whatever we know so far,

the predictor of longevity,

none of them could predict whether this CR-only mouse,

throughout day and night,

that mouse is going to live less than the night-fed mouse

that was going to live 25% extra.

Does that mean that there are biomarkers

related to longevity that we just haven't discovered yet?

Yeah, so that's exactly.

So that means whatever we know so far about biomarkers,

he could not use to predict.

Maybe there was a lot of noise.

Maybe he had to use more number of mice to get that

because you know, biomarkers are not going to predict

in every instance, or there is some error.

What is also very interesting is,

if you look at the body weight and body composition

of all these mice,

there is no difference in body weight and body composition.

Across all these different groups.

Across all these groups.

So it doesn't matter when they ate.

Provided they were sub-maintenance calorie intake,

so fewer calories than is required to maintain their weight.

Didn't matter what pattern of eating,

they were the same weight.

So that, in many ways, seems to mimic the human studies

where they say, "Look, it doesn't really matter

whether or not you use caloric restriction,

or you start your feeding window in the morning

or start your feeding window in the evening,

or you portion control for sake of weight loss."

Because we're taking a snapshot of that.

And then another thing with the human study

that we are referring to here, in that human study,

people are actually already eating within 10-hours window.

Habitually.

When they selected these people

to have them enroll in the study.

So they were already eating for 10 hours

and fasting for 14 hours.

All participants had to reduce their caloric intake,

and they reduced by almost 25%.

The CR group continued with 10-hours eating window

and the CR plus time-restricted group

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

So it's just a two-hour difference.

It's just a two-hours difference.

Okay, so I just want to make sure people can understand.

So, in this human study,

which is the one that I felt that the popular press venues,

all except one venue, got either semi-wrong or badly wrong

in terms of their conclusion,

that was my interpretation anyway,

was that either people came into the study eating

basically in a 10-hour feeding window,

which goes back to my first question,

which is that most people are not eating

in the middle of the night.

Yeah, yeah.

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

then they're sleeping during the day anyway.

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

So you're saying they either

did caloric restriction portion control

within a 10-hour window,

or another group within the study

ate sub-maintenance calories, so, caloric restriction,

CR, as we're calling it, the acronym CR,

but restricted that to an 8-hour feeding window.

And they didn't see any difference in terms of weight loss.

Yeah.

But it's not all that surprising, right?

I mean if it's just a 2-hour difference.

Yeah, exactly.

So, we have done that experiment in mice

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

many other markers.

And I was telling you about Joe Takahashi's paper

where I told you that he allowed this mice

to eat within 2 hours or 12 hours, sub-caloric diet.

2 or 12. 2 or 12, yeah,

That's dramatic.

But still he did not see change in longevity even

within those 2.

So that means when you do caloric restriction

and then, at least with mouse,

and you are within 12-hours window,

that is giving the mice the best benefit,

the optimum benefit.

And 2, 3, or 5, or 12 per mouse doesn't matter,

at least for longevity.

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