ILSI NA: FNSP 2017: Circadian Rhythm in Health and Disease – (Satchin Panda, PhD)

ILSI NA: FNSP 2017: Circadian Rhythm in Health and Disease – (Satchin Panda, PhD)

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00:00
you [Music] thank you I'm glad to be here this is my first LC meeting in DC so before I start I would like to acknowledge contribution of all these awesome people here who let's see who actually contributed to this study and my fondest mostly American Diabetes Association Hensley Foundation and Glenn Foundation so to
00:42
put the talk in the context let's think about 1,900 that's when an average American when he was born the life expectancy was only 47 years only one in hundred could expect to live up to 90 years of age one-third of all babies died before the age of five and the leading causes of death and disease was infectious disease a microbial cause of disease and that led to sanitation vaccinations and antibiotics that save life and not on average biomedical
01:13
research extends lifespan by three months for every one year of research so by 2010 the life expectancy at birth is 79 years and one in four will live up to the age of 90 but the challenge is one-third of all adults suffer from at least one non-infectious chronic disease and 80% of adults at the age of retirement is have at least two chronic diseases and that means they need treatment for at least one year or longer and what has become clear is
01:46
lifestyle contributes to disease risk so here is an opportunity that we can actually target lifestyle to prevent this disease just like we did for microbial agents but actually we don't know what is lifestyle so if I ask what is lifestyle then there will be a lot of different answers it starts from fruits and vegetables eating low cholesterol diet low fat diet etc etc and then there will be no consensus so the way we define what is lifestyle is lifestyle is what when and
02:19
how much we eat sleep and move on a daily basis and if you put everything in this framework actually a lot of we'll fit into this framework but what is interesting is this let's see oh do we and this when aspect why I am emphasizing so much and when because we actually have a timing system in our body and the best way to realize that is some of you who have the opportunity to go to bed around 9:00 or 10:00 last
02:47
night then your beats lead is a little in that and then just before you woke up your body temperature began to rise to prepare you to wake up and as soon as you opened your eyes and then got some light your melatonin level drop the cortisol level began to rise and around 10:00 or 11:00 will be your high alertness and the afternoon muscle performance will peak that's the best time to exercise and as evening goes on
03:20
your melatonin level will begin to rise core body temperature begin to drop and it will go to sleep so if you think about it almost every organ in our body has to work in absolute synchrony to to produce these deliriums in behavior physiology and metabolism and over the last 20 years this new science of circadian rhythm has given us how this whole system works and it can be summarized in a very simple slide like this so like mostly in the form of blue
03:52
light goes through our eye and then activates or research a clock that's present in the hypothalamus the base of the brain and this clock in tones and various signals to clocks present in the rest of the body to produce daily rhythms in Physiology behavior and metabolism and a few years ago we discovered a new light receptor that's present in the retina and unlike art and cons that helped us to navigate the world actually these light receptors
04:23
don't do much to navigate the world now only 5,000 of those receptors in each of our eye and these receptors are very interesting because they sense bright daylight that resets our clock this is our Lautner's and reduces depression at nighttime although we can see perfectly fine in a dimly lit room these light receptors are not that it's not that sensitive so in that way what happens is as we spend we have spent a lot of our time evolutionarily with only firelight at
04:56
evening time so this light receptors turn off sleep hormone melatonin begins to rise and we go to sleep but in modern days what is happening is we spend a lot of time most almost 87% of our time indoors based on cell phone data and during daytime we actually in gloomy indoor days for example the light here is around 200 to 300 Lux but if you just step outside even if it's cloudy it will be around 5,000 to 10,000 Lux so you can see how little light we get and these blue light receptors are not
05:26
that sensitive during daytime so in that way it reduces alertness it from most depression and mood disorders and reduces performance being stuck in a room like this for days and days and at nighttime when we have bright LED light that disrupts akkadian rhythm reduces sleep latency a sari increases sleep latency so we take a long time to go to bed and it disrupts circadian rhythm so the bottom line is light for vision is not the same as life for health and we are doing lot of work with architects
05:58
and like and engineers to figure out what are the ideal dynamic lighting indoor but what is interesting is if you look at this night time map of the US and then think okay so these guys are getting security and disruption through light and if you peer into living rooms and kitchens actually what people do is they watch TV and it all types of food so then the question is how much of circadian disruption comes from this light versus food to make a long story short few years ago almost nine years
06:31
ago we discovered that actually light is not the biggest cue to the peripheral clock all the spiritual clocks that are in the organs they actually get overlaid by food cues so that means eating at the wrong time resets all the peripheral causes the brain clock is try to light dark cycle and that can cause internal be synchrony and lead to diseases so to again give you some idea about how we look at this problem we actually use mostly Mouse as
07:04
a model system we put mice in this light-dark cycle and then after a few days we we take their liver samples in almost every one hour over 48 hours and then ask how many genes turn on and off in it on a daily basis the bottom line is nearly 20% of our genes only in the liver itself turn on and off at different time of the day so what you are seeing here is each line is one gene when it's yellow it turns on when it's purple it's done self so that means just imagine all the traffic lights in DC
07:35
they're turning on and off or going between green and red to make traffic flow smoothly imagine if they're stuck in red or if they're stuck in green then the traffic there will be chaos so similarly we think that these rhythms actually help to coordinate metabolism so basically there are two major ways that the security and rhythm of these rhythms or oscillation in gene expression or protein function or enzyme function help us one is temporal separation of incompatible process that means we
08:05
cannot for example you cannot make fat and break down fat at the same time biochemically they are incompatible so that's why they have time to different time of the day and then the second is in many enzymatic pathways in many metabolic pathways there are ten twenty or thirty different enzymes and if they turn on and off at different time of the day then you can accumulate intermediate toxic products that can cause internal harm so having all this gene expressed in a synchrony actually helps to
08:36
increase what we call metabolic flux so if we think that way then we actually evolved with for mostly during day time and fasting during night time and the question is is this continuous eating throughout their night they stopped at metabolic efficiency and predispose us to obesity diabetes etc so as I told you we are a basic science lab we work with mostly mice so we went back to mice and then I'll give you why we think this way so nutrition research is there are two
09:08
major experiments that have driven nutrition research over the last hundred years then those two are one take identical set of mice give one group of mice less calorie those mice live longer and have better health so that led to counting calories and all these things about about counting calories that has been driving the economy for a long time the second experiment that actually again was very influential is this if take two groups of mice genetically identical give one set of my standard diet another set of mice high fat diet
09:40
we can substitute for high fructose high a high cholesterol any kind of diet and the bottom line is the second group of mice becomes unhealthy within nine to ten weeks they become obese diabetic and they are actually modeled for many diseases there are eleven thousand papers based on this high carb diet induced obesity what is interesting is if we look at the eating pattern of Mouse on a standard diet they mostly eat at night because these are nocturnal animals but my son high fat high fructose high
10:12
saker's diet they actually split their diet 5050 between day and night so as a result what happens is the see carrion clock or the gene expression rhythms in liver in heart and all this metabolic organs are very robust in standard diet third mice whereas in high fat diet fed mice they become dampen so the question we asked is how much of this is how much of the disease is due to diet versus hitting pattern so now I'll give you some example or summarize how place the
10:44
mouse metabolism or to some extent human metabolism works throughout there and night for example if a person is three meals a day and as soon as we eat breakfast our body actually turns into a carb burning mode so we are mostly using car from readily available sugar enough in a meal throughout the day and during this time are actually fat burning is pretty low and as fasting goes on then we switch from sugar to fat so now imagine if I take the same three meals
11:15
and then spread it over a longer period of time then what happens is the switch from sugar bonding to fat-burning will take a longer time or will be delayed and it will not be enough for fat-burning to come to full speed so now if we compare them side by side you can see if somebody or a mouse is eating say ten hours every day and versus 15 hours every day then you can see a slight difference in fat burning and over days or over weeks that can actually have significant effect so to
11:47
test this hypothesis we did a very simple experiment we took genetically identical set of mice even from the same vivarium from the same room so they have the same microbiome to begin with one set of mice got a high fat diet ad libitum so they can eat whatever they want the second set of mice were actually trained to eat the same number of calories from the same food source only within eight hours every night in the first experiment we did this for 18 weeks every week device where where the
12:19
food was where to make sure that they add the same number of calories at the end of 18 weeks this is what we find that demise that ate within eight hours they were 28% less and they have 72 percent or 70 percent less adiposity if we look that there when we look at their liver and this my son high-fat libitum were filled with fat whereas the mice on time restricted feeding what we call were pretty healthy and in fact if we just compare the liver sections from
12:50
normal diet fed mice and high third-time restricted you cannot see the difference so that was the extent of difference and to go back actually the experiment had four different cohorts there are also mice with normal shell ad libitum and normal child kind restricted and high fat or libitum Hypertime restricted and all these four groups of mice at the same number of calories and they had similar pattern of activity 12 day and night the only difference was in their weight and we actually went ahead and did very thorough biochemical analysis
13:21
of this liver at different time of the day and basically the bottom line is if we measure the 300 metabolites from this liver between any two groups for example even if we give normal Chow or deliver two more timeless leaders 15 percent of liver metabolites are changing significantly between groups even on normal diet and on high fat diet nearly 40 percent of metabolites change just based on climbing up food intake and most of these metabolize their change this is the heat map representation and
13:52
you can see these two groups actually change the most sugar and nucleotide metabolism and fatty acid metabolism the bottom line is in most of our chronic diseases that driven by changes in fatty acid metabolism or cholesterol metabolism and sugar metabolism so that's why we're very excited about what's going on so these are four different groups of mice the bottom line is if you look at under high fat diet ad libitum many of these metabolites particularly sugar metabolites are pretty low and these are actually good metabolites for
14:25
sugar and those are increased on the time restricted feeding and conversely in high cut diet if we just give food only for eight hours then this metabolize these fatty acids which are very harmful actually reduced and heatmaps don't give you the actual magnitude of change and to show how different these changes are these are essentially eight different time points for each group and you can see for example coenzyme a goes up and down by
14:55
almost 40 fault depending on time of the day so this also has his implication for people who are interested in looking at metabolites in human samples or in animal samples depending on the time of the day many of the metabolites will change significantly so that's why controlling simply for time of day when you're doing analysis is very important and if we just map them unknown metabolic pathways this big metabolic pathway chart that you see once in a while on wall paper and then put the
15:26
genes that are involved in this metabolism then almost all these green ones are the genes and then the black ones here metabolize all of these actually change on a daily basis based on whether the mice eat on a time restricted or ad libitum fashion so the summary of this first paper was the body fat reduce body weight reduced blood sugar and blood cholesterol reduced energy expenditure actually increases under time restricted feeding motor control improves and endurance improves so after this we kind of
15:57
loosely use this term time distribute feeding without knowing that this would actually take off and now TRF has or tre has become a standard term in many websites so the concept is timing of food access is restricted know of what attempt to restrict calorie or change nutrition and this is just experimental model in animals and it can prevent obesity and metabolic disease in many different conditions so then there are lot of different questions one was whether it's therapeutic of course it was preventative can is it Kara beauty
16:29
is eighty hours a magic number or can memorize it for nine ten eleven twelve or fifteen hours and is it effective against other nutrients for example high fructose ice across high cholesterol diet so to tell this we went back to the vivarium had nearly 600 bison different cohorts so we tried either high fat high sucrose or high fructose diet and then to test whether eight hours is a good number we tried nine 12 and 15 hours to see
17:00
legacy effect or reversal we actually felt mice time restricted for five days and two days they had oft so they could be injured in the weekend and then we also did the classic crossover where they were time restricted initially and not lived in the second half or vice versa so the bottom line is all these cohorts at the same amount of calories from the same food source and in fact the mice that eat beans it over the weekend they eat more than mice that live at them throughout the day throughout the week so the bottom line
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is when we put time restricted feeding on any cohort then the body weight reduces and most of the body weight reduction is due to reduction in body fat so that's the MRI body composition analysis of all these mice at the end of the experiment and again this nine hours and 12 hours time restricted fitting works even five days of time restricted and two days of beans eating was preventative although these mice ate more then ad libitum failed miles and 15 hours actually doesn't work that well and this is the most important
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experiment where we actually are delivered mice for up to 26 weeks these mice become really big 55 grams of mice is not as not a small thing and then if you put them on time mr. fitting they lose nearly 20% body weight within the next 12 to 13 weeks and if we do the experiment early on in their life we can completely reverse the body weight and conversely it demise for actually healthy there were time restricted fed up to 26 weeks they will again wait when they go back to our libitum so that means there is no legacy effect they
18:35
have to be on this time there today eating pattern if the mice at normal diet although you don't see much body with difference what is interesting is if you look at the muscle mass my son normal diet they increase their muscle mass much more than any other group so then the question is is it only on liver and muscle that the effect is and in fact the effect is pervasive this is white adipose tissue and these are all inflammatory macrophages getting into white adipose tissue and our lipid threat condition and those disappear in
19:06
brown adipose tissue we see browning of brown fat so that means this might actually produce a lot of heat they literally burn the fat and in fact that's what we see in the vo2 consumption rate and now focus on only three parameters as I told you cholesterol free fatty acid and and blood glucose those three are drivers of health and disease and the bottom line is under time restricted filling we do see serum cholesterol always drops in fact this is almost a biomarker of time restricted feeding for us now because
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any genotype of mouse we put on PRF we see this reduction in serum cholesterol the same thing happens with an liver triglyceride of liver free fatty acid there is actually much bigger drop in liver free fatty acid than in the serum triglyceride and that's expected because the serum triglyceride is tightly controlled it doesn't fluctuate as high as in liver triglyceride and the blood glucose again we see postprandial blood glucose
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typically attenuated on the time restricted filling so finally you might ask well this mice are fasting for 16 hours or 12 hours at the healthy can they actually do stay on treadmill or can they lift weight and in fact the grip strength which is equivalent to lifting weight doesn't change their they can lift as much weight as normal childhood mice but what is interesting is this if you put a mouse on treadmills this mouse will run for 75 minutes if they ate standard diet
20:38
if they eat high fat diet they run only for 15 minutes of course the performance is reduced but if they eat the same high-fat diet under 9 hours of 10 hours they actually outrun the normal childhood mice by almost doubled time and this was always surprising and this effect happens only when they eat 9 to 10 hours if they eat the same diet for 12 hours that effect goes away so going back to the mice what we find is the nine-hour eating or 10
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hour eating slightly increases ketone bodies and this is what nutrition is we usually discard because this is a very small increase but we think that small increase every day is driving this exercise performance so the bottom line is time restricted filling is preventative and therapeutic but it doesn't have legacy effects so that means if you have this fat Mouse going into time restricted feeding can lose weight but if they lose my if the lean
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mouse goes into ad libitum feeding there and it will actually gain weight so then the question from reviewers was well mice and nocturnal he wants a diurnal maybe this is a nocturnal animal phenotype and so that's why we stepped down he went to flies and then we did timeless repeating in flies so flies actually during their time and if we do time literal feeding then we feed them only for 12 hours they eat the same number of calories and flies do gain
22:12
weight over five weeks and these TRX lies don't gain weight and they actually had same amount of activity but what is interesting is they get into deeper sleep so every day by five weeks of is most of the Flies throughout the world while living in this small vials they barely sleep for three to four hours but if your time restrict them only during the daytime they have good night's sleep they can sleep up to six to seven hours during night time and what we find is this increase in sleep is only due to
22:43
change in arousal threshold so that means they get into deeper sleep and they don't get disturbed by other flies flipping their wings nearby but what is most exciting for us was we could actually go and quantitatively as a Drosophila heart function so Drosophila heart is very similar to human heart in development and function the only difference is it's different in structure and the nice thing is you can decapitate the fly open up the body cavity and monitor the beating heart for
23:14
up to 12 hours and that gives us enough time to look at how the fly hatch works okay so it's playing the video so this is the type of video that we see we take one pixel width of this image and then line them up right next to each other to get what we call it M mode emails then these from these M mode images we can extract many parameters for example we can get diastolic diameter systolic diameter diastolic interval systolic interval heart period and then I'd miss
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it index and fractional shortening all the seven parameters parallel very well human heart condition and in fact a splice is just like as we as this seven parameters change in a very predictable fashion so then we asked how time retrofitting effect these seven different parameters so I showed you the video of how the ellipsoid fly is at three weeks and now let's look at how the heart actually functions at five weeks of age which is around middle age
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45 to 50 years for a human and you can see the heart is very rhythmic it barely beats sometimes and you wonder whether this is still alive and it's lies it only for 12 hours every day then we'll see how the heart beats and this is fairly regular actually they have very little added m'q index so in fact we do this at different ages so the bottom line is we can slow down ply aging hard by almost two weeks which is around 30% improvement in their aging
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that so they'll slower so with that we went back to mice and asked a similar question a high cholesterol fed Mouse is a very nice model for atherosclerosis so we took this micelle deal with septal knockout mouse and then give diet that had one point two five percent cholesterol by weight which is very high and just like in other strengths we do see although they eat the same number of calories they actually weigh less most of the reduction is body weight is due to reduction in fat mass and actually LDL receptor knockout mice gain lot of
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muscle mass and just like in other experiments they also gain this treadmill performance if they eat for eight to nine hours and the most exciting thing is we can actually reduce a330 plaque in the aorta by almost 40 percent if they add the same high cholesterol diet but eat it within eight to ten hours interval so in summary from Mouse and flies we found many different benefits of time wasted feeding actually didn't talk about dysbiosis one big
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thing about these biases that we find in PRF mice is at least in mice fiber is digested in the upper intestine and is observed whereas under time restricted feeding for some reason fiber actually gets to the cecum and that's where it's digested but there is no good absorption of sugars so these mice actually excrete some free sugar in their stool so in that way PRF reduces absorption of blood sugar from nutrition it also changes the guard my authority got microbiome in
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certain ways so that the bile acid metabolism is changed so with this and then we asked well can we go back to this hypothesis does eating time matter in human and actually over the last several years we have seen a lot of papers coming out in top journals in circadian rhythm and most of these studies many of them as we relate to mostly model organisms so and particularly when it comes to nutrition and circadian rhythm nearly
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all of them were model organisms so that's why we started from scratch one thing we realized is in many nutrition research people are asked what do you eat for breakfast lunch and dinner and they rarely asked what time did you eat what so to get that timestamp we actually wrote a very simple app this is a very old version of the app and the bottom line was we have to make the app as simple as possible just like Amazon Checkout one-click checkout so one-click was to open the app second click was to
27:24
take a picture of the food that the person was eating and then the third click was to sale and they didn't have to uh note that what it is they didn't have to say how much they ate but in case the forgot they could actually go back and text it select from the menu and so in that way we transferred the burden of annotating food from the user to the researcher and with that we actually we recruited around 156 adults who are non shift workers and not
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related to anyone in UCSB Salk or any comic company in San Diego and they were not also not related to them and we asked them to record everything that they ate or drank for three weeks because we know the eating pattern changes from week to week and we had some error estimation approach so for example every day we would send at random time a very simple push notification did you eat or drink something in the last thirty minutes they are to just say yes or no and then
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we compare the response with what whether they recorded anything or not and from there we got the error estimate of 10% so that means 10% of the time they ate or drank something but forgot to log and so we got nearly people actually logged all types of food so these are the pictures random pictures of people log input and as you can see for some of this food it will be extremely hard for them to actually pull a food name and then find how much quantity they ate
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and they won't be actually inspired to log that but taking picture was very simple so we've got nearly 36,000 entries out of which 20% were water and 28% prepackaged food so we could actually extract the nutrition information easily and then 50% were mixed meals so that's where we used multiple approaches we put the pictures in Amazon M torque and also we have three independent researchers they independently assess how much calories were there on an average they ate nearly nineteen hundred forty five kilo
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calories which is very similar to what you would expect but again we had 10% false reporting so we know that the weighting more than that and just the act of recording data did not change their BMI over three weeks and then the question is how do you represent this data timing of food information so what we do is we we plot them a long timeline and we call it feed o gram so we also estimated that it takes on an average 14 minutes to finish an average meal or average snack so that means within 15
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minutes if somebody's sending multiple pictures that is considered as one eating event so this is someone's kilogram over three weeks and it's really random and those are the week then we can eating events and if you look at it then you can begin to see how the eating pattern is between weekday and weekend and now if you combine this and then plot it on a radial plot this is 21 days of data from one individual and it goes from the top one is morning 6:00 a.m.
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that's noon and then this is evening and midnight these 156 people's data over three weeks so as expected the number of events Peaks around one o'clock when people at lunch and again around 7:00 or 8:00 when they eat their dinner and the number of calories per event actually Peaks predictably but the midnight snacks are very dense in calories so since we had the timestamp we can also go back and see what kind of food people prefer to eat at for time and now we can actually
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go back and see in which ship code what people prefer to eat for breakfast lunch and dinner and I just draw your attention to one does the drugs think not sure whether the drugs are here yes medications and supplements what we find is people remember their medication only during breakfast and just before going to bed why this is important is nearly 70 percent of fda-approved drug targets a circadian so that means the efficacy of the drug is strongly modulated by
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time of the day when the drug is taken and in fact in animal models we can show that a drug can be therapeutic at certain time and can be toxic at another time so in future it will be interesting to go back and look at these drugs and compare what time the target is speaking or is at its trough and what time they taking the drug so now the question is how do you figure out now eating pattern and can you can you express it in one bit one parameter so the way we define it in duration is the interval in which
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90 percent of for over two to three weeks is consumed so that means if a person actually starts eating from 7:00 a.m. to 10:00 p.m. that's the 90% interval then there will be around 15 hours interval and what we found among this one in 56 people 50% of adults eat for 15 hours are longer and in animal experiments if this animals are given 15 hours of Katty food or high fructose diet then they would become they would
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become sick now the question is how people eat during weekday and weekend since we actually give them another active was that they were wearing so we can figure out what time they woke up for time they went to bed the bottom line is in the weekend people actually delay their breakfast by up to two hours 25% of people believe that breakfast by two hours how does it why does it matter just like our brain has a clock and when we travel over to time zones we sleep with pattern gets disturbed when we eat breakfast two to three hours later in
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the weekend we suspect that our liver clog gets disrupted and we don't even feel it that easily and the dinner time actually doesn't change over the weekend now you can ask since we had the first the time stands in the calorie content we can ask another question by noon of every day what percentage of belly calorie is consumed and it's only less than qualified percent of calories consumed by noon why this is important is a body is most efficient in digesting
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food insulin response is much better in the first half of the day and that's when we are consuming less food and by evening we consume nearly sixty two percent of four and the first three hours of evening we consume more food that in the first six hours seven hours of the day so this is the worst time to eat food and we actually consume a lot of food in the evening okay so then we also have the timestamp of when the person woke up and when the person actually had the first calorie and if we look at that as soon as we work wake up
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within one hour of waking up 80% of people eat or drink something that has calories and within two hours of before going to bed 50% of people eat or drink something so the bottom line is as long as our eyes are open our mouth is open and there is a trend in how this eating pattern changes over is and also in different ethnic background and different BMI I won't go into detail we
34:36
did a similar study in India and we find very similar trend and in fact in India and nearly 60% of people eat for 15 hours or longer so the eating duration is much longer because people wake up early and also they go to bed very late another interesting thing that we found in India is although we excluded shift worker we found people who are eating very randomly throughout 24 hours and when we went back and asked they said they don't do shift work but their spouses do so that means there is lot of second hand shift work that goes on in
35:07
the society that's not counted by DLS Department of Labor Statistics that's another thing that we have to keep in mind so then the question is does BMI correlate with eating duration the answer is no it doesn't correlate because BMI is a very complex outcome but we asked a different question if a person has a BMI of about 25 and it's for 14 hours or longer can we change it in and is it a modifiable behavior and if they do modify the behavior does it have
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positive outcome so the bottom line is can we actually sink this human and so we took eight subjects this was very preliminary pilot study and we asked them to eat only for 10 hours every day for 16 weeks they could eat whatever they want how much ever they want this is how to eat for self-selected 10 hours so this is a photogram during baseline and this is a photograph of the same person giving intervention and you can see that the person actually changed its eating
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interval so these are the eight individuals that shows different time of the day depending on their lifestyle the bottom line is after 16 weeks they lost nearly 3.8 percent of their body weight they're not super obese but the overweight what is exciting is between 16 weeks and one year we actually let them lose there is no contact with them and at one year they still maintain that body work again a loss and when we asked why did you stick to this hitting pattern the surprising thing was it was
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not due to body weight loss they said they slept better and they felt more energetic throughout the day and that drove the behavior so it's possible that sometimes your target outcome may being one thing but what they feel on a daily basis may be something else that drives the behavior so in summary although these people reduce their eating interval to 10 hours it's actually not mechanistic because many of them reduce their calorie intake also by 20% so it
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remains inconclusive whether time restriction or caloric restriction caused this outcome but if PR leads to see us then who cares means if they can improve if they can reduce calorie by this way then it's much better so right now we have actually expanded this study previously it was only in iOS now it's runs both on iOS and Android people have to go to this website for my CKD and clock because we wanted to reduce the number of people who just impulsively download an app and never use it but
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according to HIPAA law we have to mention their privacy so after the sign up they have to answer a few questions we send them there in pom-poms and I met by email and then they also get activation code they start logging so we get the depository was done very locally and now we have participants all over the US and also actually all over the world and hopefully we can collect enough data to inspect least other researchers to start
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looking at when people eat and how to let's do their health and with that I'll stop and take some questions thank you George Anthony Campbell Soup Company thank you for a very interesting talk if I was tracking your last study I understood that with time restricted feeding irrespective of the time selected it you know eating within a 10 hour period you saw good results have you done any work to kind of look at the
38:44
interaction between sort of the you know the croteau biology aspect and time restricted feeding that is so that it you know for people that selected within 10 hours during light cycle were there results better than those is likely to say 10 hours in you know what would be our Dorf cycle yeah so we haven't done the studies ourselves what other people have done in many weight loss studies people have gone back and retrospectively looked at when people reported their lunch or dinner and what
39:14
they're finding is people who eat later in the day even though they're trying to lose where they have poor outcome than people who eat earlier in the day and that makes sense based on insulin response being sick adrian in melatonin having an interaction with insulin system so the same way if you can restrict it during the day you're going to be better off yeah it is tipping anytime is better than if you want to go to the better goalpost and during the day is better Michael McBurney DSM very
39:47
interesting we see lots of articles now talking about sleep and sleep length related to health and body mass so do you think measure of sleep is a marker of fasting or not eating and you have thoughts on that yes there are two aspects one is sleep can be an indirect marker of how long people are eating but there are some very nice control studies done where if an individual is
40:20
habitually sleeping say eight hours and they are forced to sleep only for five to six hours then they of course they will try to eat because our body reacts will say well you are staying awake so you need some energy and these people will eat but what is interesting is the amount of calories we eat to account for that reduction in slip time over suits what is required to stay awake so that means our hunger and satiety system
40:52
somehow doesn't work properly to stop when to stop and those guys over it so there may be two different aspects they may be overeating to compensate for this a wake time my question is actually a little bit related to Mike's question so first of all thank you great great talk so my question so first I had a comment because I think David Dingess from the University of Pennsylvania has a lot of evidence to substantiate the pilot study
41:24
that he has because he looked back at all the studies they've done on shift workers and sleep and he has 20 years of data showing that the people who didn't sleep enough and ate actually an extended their eating period or gaining more ways than the others so you could you can you could be even if your study your files that he was not conclusive I think there are others especially David dangers who could substantiate a lot of your own hypothesis and second to
41:56
elaborate on Michael's question I wonder if it's not if it's not an interplay between the two because the hormones that actually the dictate like the society etc they're also involved in the sleep and the quality of sleep so I'm wondering if there is any benefit into doing a study that is looking at the time the duration of the eating and also at the duration of the sleep and the quality of the
42:27
sleep and whether some collaboration with the sleep researchers could actually enlighten us a lot in terms of what's going on there because it's the same body that sleeves and eat so it is probably probably not independent factors yeah you are right on because the orexin system does regulate both hunger satiety and sleep it's not only CNS a lot also happens in papery for example a lot of our human volunteers who try to eat
42:58
within say 8 10 or 12 hours one thing that they always report is the acid reflux goes down and and if you think a lot of people actually it cannot sleep or wake up in the middle of the night because of god problem and by reducing it in duration if you increase if you improve got health that also helps sleep better so it's kind of a chicken and egg story because if they eat within certain number of hours
43:30
they're sleeping better and conversely they sleep better and sleep longer they also automatically reduce their eating duration so obviously it is to interact and God might be another access to which they enjoyed Thank You Theresa Davis from Baylor College of Medicine so I have two questions one in that last study that you described where people were asking to eat within the ten hour period do you know if their caloric intake within that study was similar and the second question is you know about
44:02
how within that 10 hour period how for example the protein was balanced throughout the day because we know from recent studies that if protein intake is more equally balanced throughout the day rather than the small protein in the morning and a lot of protein in the evening the way people typically eat at protein math is better preserved in older adults yes so going back to the first question I think in my last slide I had oh sorry excuse Icicle in fact
44:32
when they reduce 18 time duration they also reduced calorie and for various reasons one is most of the calorie reduction happen from say alcohol and let my dessert because they cannot eat or drink that so in that way we achieve two things reduction in calories and improvement in overall nutrition second thing that happens is since they go through almost 14 hours of fasting and the morning they are well prepared to eat the breakfast they actually have a
45:03
bigger breakfast than before and breakfast is the in what we see breakfast is the meal on which individual has complete control because once you get out of the house it's hard to control your nutrition so what happens not only they increase the size of the breakfast the quality of breakfast also improves so this is an interesting approach that you change timing and they automatically change many things that are desirable from nutrition point of view coming to your
45:34
second question since we see on a population level people are eating very less before noon whether it's protein carb or that it doesn't matter if we can change that equation so that as I said if they have longer fasting and have a bigger breakfast automatically they will increase their protein intake in morning so I think this might be an indirect way to achieve some of the stuff that nutritionists have been trying to do thank you chosen cubed Ilse North America Saji
46:07
based on what you know about circadian rhythm for somebody who is a diabetic what is the best time for them to have that carbohydrate intake in terms of how should they spread it out that's a very tough question because whatever I'll answer is based on my guesstimate if you're talking about type 2 diabetes then even in type 2 diabetic there is still a circadian rhythm in insulin response so in that way
46:39
sifting more of that food towards the morning is desirable and in fact we have a few type-2 diabetic and in fact some type 1 diabetes with insulin pump or trying to do TRS and they always report that if they eat later into the night then their insulin is more out of control so I think even bringing that to as early as a last meal before 6:00 or 7:00 is much more desirable but these
47:10
are all anecdotes and we still have to wait to see a real well controlled study a clinical study so we'll just do it's just so interesting raises many questions there's some people that get up and may have a cup of coffee but they don't actually eat breakfast for several or their first meal for several hours have you looked at weather activity followed by you know that 14 hours being you know 18 hours into your day is that
47:40
make a difference or not yeah so this is a question that comes up very frequently so there isn't so in our study we actually counted coffee as calories for many reasons one is since they were just taking a picture we could not figure out whether it hurt sugar or not so we aired on the other side but there is a very nice study from Ruth Patterson who went back looked at enhanced data at prospective data on women's health
48:13
and see discounted coffee so coffee doesn't count as calorie and in her study what she found is women who passed for thirteen hours overnight and they have much lower breast cancer risk than women who eat for more than say 11 hours and fast for less than 13 hours and then in a second study women breast cancer patients who are going through treatment if they passed for 13 hours are longer
48:44
than they have much better prognosis so those two analysis are done discounting coffee whether with or without sugar and cream a silver and cream so in that way at least there is some benefit of fasting with coffee but in terms of really going into nitty-gritty detail if you want to get the maximum benefit then again we have to think about it we have to do a good study hi Stella Volpe Drexel University nice presentation
49:16
two-part question one is sort of going off at your son question is that did you measure diet quality at all and then secondly did you also measure whether for example they had more protein in the morning or more carbohydrate or combination so I realized that I mean this work is great and it's so interesting but I don't know did you do those next step yes or miss steps yet or have others and also activity level because who or Highmore highly active would eat more and perhaps later in the night than others who are less active
49:48
due to their activity so are you questioning yes so to your first question we did not look at nutrition quality or because once you include that in the manuscript then the reviewers will ask for interaction and we are not powered for that so that's why we stayed away from that but now that we are not the only ones that are at least seven or eight different clinical studies going on in Australia Europe and us to our knowledge there may be more and they are
50:20
doing a much better job in looking at nutrition and climbing interaction activity we actually had a active watch on many of the participants so we have activity data what is interesting is after the do TRS since they're feeling more energetic throughout the day and particularly the middle-aged and older adults who have a little bit of knee problems or a little bit of pain that pain goes away because of reduction in systemic inflammation so the activity level increases slightly so
50:52
it's very hard to say but coming back to your last question evening activity and late night eating actually we are more prone to we are more designed to be more active towards the end of the day and that activity just among normal people I am NOT talking about people who are going to gym and running for one and a half hour two hours but normal people it's not a big deal if they stop eating around 6:00 or 7:00 because that will actually take care of their sugar much better so we haven't gone into looking
51:23
at high intensity athletes who do intense activity too at the end of the day and how is the body composition affected thank you right this about to be the last question and I'll let Chuck go cause he's a toxicologist well last night I didn't recognize you and we had totally different conversation of the general I've been a fan of your work for years the going back to I'm a
51:53
toxicologist and caloric restriction back about 20 years ago was really open eyes to many when we found that for example 70% of liver could be removed and later challenged with the chemical of pettite oxidant that the animal would survive there would be little injury and that this could be replicated through dietary restriction by limiting number
52:26
of calories in animals and survived a chemical insult much easier and as a lot of new research has shown that there's decrease in disease with people at under caloric restriction and now it's been used as possible therapy with for treating breast cancer I'm curious as to other interventions as
52:54
well as for example after as treatment for various toxicities has that been considered yeah so I'll give you two parts answer one is and many of the calorie restriction studies in rodents and higher animals are actually time restriction as well in fact there's a very recent paper in Cell Metabolism showing if CR is done on mice usually
53:27
the way CR is done you give 70 percent of the ad lib diet at certain time of the day and in most laboratories around in the afternoon 5 o clock and mice eat that food within 3 hours so they are actually on at three hours time restriction so now if you replicate the same three hours time restriction or calorie restriction in morning versus evening the morning fed mice who are eating during day time they do not lose weight even though their calorie restricted only the evening fed
53:59
mice lose weight as is reported by many CS studies so it will be interesting to go back and do the toxicology to see whether the day fed mice are more or less resistant to relative to night fed mice and coming to time restriction we actually don't have the answer whether they will metabolize much better or worse but what we do see is a lot of sip 7 cytochrome p450s that are strongly c kadian in liver and amplitude of
54:32
oscillation goes up under time restricted feeding relative to our libitum feeding so based on that I would suspect that they can metabolize break down toxic products much better than ugly fed mice and in fact cholesterol great bound by cytochrome p450 67 acid 7b is pretty high in this TRS mice and that's correlates very well with hepatic cholesterol being broken down to pilots in this mind so our suspect they would
55:03
be much better registrant reductions thank you thank you I'm just curious a one short thing back about eight years ago you said that you only ate between eight and eight do you still recommend the certain times time limit for caloric consumption now I add ins we have very limited data to recommend anything but you can take away from this presentation and try on yourself because a lot of people who try it and then come back and tell me whether they have benefits or
55:35
not thank you all right well thank you

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