THE ASPEN INSTITUTE ASPEN IDEAS FESTIVAL 2015 WARNING: TECHNOLOGY MIGHT BE HAZARDOUS TO YOUR HEALTH. Kaufman Room Doerr-Hosier Center Aspen, Colorado

Transcription

1 THE ASPEN INSTITUTE ASPEN IDEAS FESTIVAL 2015 WARNING: TECHNOLOGY MIGHT BE HAZARDOUS TO YOUR HEALTH Kaufman Room Doerr-Hosier Center Aspen, Colorado Saturday, July 4,

2 LIST OF PARTICIPANTS: GENE D. BLOCK Chancellor, University of California, Los Angeles Professor of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine, UCLA * * * * * 2

3 WARNING: TECHNOLOGY MIGHT BE HAZARDOUS TO YOUR HEALTH MR. BLOCK: This is July 4th. I realize it's the end. I'm amazed there are as many people here as there was -- I -- when I looked at the time I was speaking I thought two people -- two people. So it's great. And this is going to -- hopefully this will be fun. And it's serious, but it's half-serious because it's really looking at the dangers of technology rather than the advantages, so. And I'm Gene Block. So I'm the chancellor of UCLA, so that's sort of my day job. But I run a lab studying biological timing -- my evening job. And I've been able to keep pretty active in the lab until recently when things have gotten so busy at UCLA that I barely get into the lab. But I remain passionate about this. So I hope it will be fun for me to talk about. So it's of course clear that technology is changing our lives and in almost every way technology is improving our lives. And everything from having now brightly lit cities -- so bright in fact in Hong Kong there's actually concern about how bright it is because you can't even get your bedroom dark -- to -- you know, very common now -- you know, read in bed on your computer, your tablet to, you know, Eyewatches, to easy, convenient, safe travel across time zones, to 24-hour operations. You get on the phone, you call United Airlines, and you're talking to someone probably in India who's working during their evening actually, but just seamless where 24-hour operations occur. So technology has made us more productive, has made us healthier in many ways, and certainly there's no argument that technology is a great force for mankind. However, it is having some impact on a system that controls your behavior, profoundly affects your physiology called biological clocks which are indigenous clocks in your body that evolved over time. At a time when we weren't crossing time zones, we weren't working in the evening, there was daylight and then there was struggling with evening when you couldn't see anything. I mean there was no artificial lighting during the evolution of biological clocks, there was no time zone travel. So this is all highly unusual environment for a human system that's evolved under very different conditions. So what do we have now? So we have something called circadian disruption. 3

4 I'm going to talk about that, what it means when this very sophisticated timing system that governs your physiology becomes disrupted. And there's a lot of reasons for that disruption. Everything, as I mentioned, from your brightly lit cities to interior of your house now is increasingly having bright white light because of new light-emitting diodes changing from sort of yellowish light to this white is much more impactful on your timing system, so I'd say, you know, huge TVs that are extraordinarily bright, to computer tablets, as I said, to continuous operations, to global traveling. All those technological advances that are so positive in so many ways is actually having an impact on biological timing. And the impact is -- actually we're recognizing is more serious than anyone had anticipated in earlier era. So what's one outcome of circadian disruption? Well, one outcome which is not great is obesity. And mice, who you disrupt their circadian system by a little bit of light at night -- and we'll come to that at the end of my lecture -- gain weight when mice that don't experience light during the evening don't gain weight. There is a huge impact on metabolism of disrupting circadian rhythms, and not just disrupting it by traveling across time zones, but even just changing the amount of illumination you receive in the evening to something I said is getting increasingly common. So just start off by talking a little bit about biological clocks and then we'll look at the phenomenon of circadian disruption. So within organisms, within higher organisms there are a number of biological clocks. Biological clocks are internal physiological timers. So when you go to the ocean and you look at intertidal animals, amazingly they've got a lunar clock, many of them intertidal clock they could actually internally predict the height of tides in California. Actually their brain calculates the height of tide so they get out at the right time in their environment. But for humans the biological clock -- although it's misused sometimes to talk about aging -- but the biological clock, as it's commonly referred to, is really a 24-hour clock, a circadian clock -- circadian -- which means about 24 hours -- not exactly 24 hours, about 24 hours. So we all have within our body a clock -- actually 4

5 you're going to see clocks that actually have a periodicity, an internal periodicity of just a little longer than 24 hours. So you have in your body a system that generates 24 hours -- just like an alarm clock, you know, your physical alarm clock. You actually have the same system -- timing system built in but it does -- it's not exactly 24 hours, it's about 24 hours and it gets corrected each day by the light cycle. So this clock -- if you go, for example, into a bunker -- and in Germany, Max Planck Institute in the 1960s and '70s there were students who volunteered -- and this is amazing to volunteer to do this -- they go into a bunker for a month. They did this usually because of free food, they could study. And they never did it again, no one ever volunteered to do this again after a month because one thing you had a rectal probe which was terrible, because we wanted to measure body temperature. But they looked at people and sure enough, if you keep people in continuous dim illumination and no noise -- these bunkers were underground and I've seen them -- amazing -- you couldn't hear anything so there was no way of telling the time of day. You woke up about a half hour later each day. So this internal timing system was about a half hour late each day. So that's true of most humans -- your biological clock is a little longer than 24 hours. But when you're in society, in the environment, if you get bright light, the light resets your clock each day to exactly 24 hours. So you got this internal clock called the circadian clock and that governs an extraordinary amount of our physiology and behavior. And this is hard to see in the back and I'll just talk through it so you can see what it is that nearly all sort of cognitive functioning and physiological functioning exhibits 24-hour rhythms. It's hard to find a variable, a physiological variable that isn't rhythmic. So if you look at core body temperature you have this rhythm that peaks actually during the late day and falls during the evening. In fact the reason you're able to sleep well is your body temperature rhythm is falling at night. Plasma melatonin -- so melatonin turns out to be pretty important in a number of ways in the human body. And sure enough the melatonin levels are very low during the daytime and then at nighttime rise to high levels and 5

6 then follows this very clear rhythm in melatonin. Sit there with an ipad at night and that melatonin rhythm that normally is fairly high at night gets suppressed. It reduces the level of melatonin. So again night lighting will disrupt this rhythm. If you look at, you know, sleepiness scale you get more tired as the day progresses and this -- that's a rhythm, it's not just that you've been up. This is at night, you're always more tired even if you slept during the day. Your vigilance, your reaction time goes down at night pretty dramatically, your cognitive throughput, your ability to add random numbers goes down at night. And it doesn't matter whether you've been up all day. It's not fatigue. It's a circadian rhythm in performance. And that's the amazing thing about this. This isn't just that you've been up all day so you're tired so at night you misperform. Literally if you sleep during the day you still do more poorly at tight. So truck drivers, for example, often go -- run off the road at 5:00 o'clock in the morning. So most of the accidents occur right at the time of dawn -- it's called the dawn effect that no one's ever really understood it. But it turns out there's an extremely low point in your alertness. You're actually at a very low point. And even if a driver has slept properly and legally during the day or early evening, wakes up, and at 5:00 o'clock in the morning can't perform very well. And it's not because of fatigue. Fatigue is a problem, certainly, but it's really because there was actually a rhythm in your performance, you were not designed to work at night. It's that simple. You know, your system optimizes your attentions during the day and minimizes some of these functions at night. So the body is profoundly rhythmic and you almost can't find a measure that doesn't observe this 24-hour rhythm -- circadian rhythm. So how is this rhythm generated? And this story today is so different than it was 20 years ago. If I was giving this lecture 20 years ago, this would be a really simple story. I would say there was a part of your brain that generates as a biological clock that generates these 24-hour rhythms. And this -- part of the clock -- and this -- that's partly true now -- there is a structure at the base of the hypothalamus. So here's the 6

7 brain, the base of the hypothalamus is called the suprachiasmatic nucleus -- an SCN -- simple -- SCN -- suprachiasmatic SCN and the SCN generates 24-hour rhythms. This is a tissue -- neurons -- neurons -- collection of cells and nucleus is a collection of neurons -- and those cells, many of them individually can generate 24-hour rhythms. So it's actually miraculous when you see these cells at work. They generate this 24-hour rhythm and that rhythm which is about -- let's say about 24.5 hours gets reset each day by light going to your retina and then via pathway to the SCN resets the clock just like a clock that's not accurate every day you reset it. When I went to school, which abates me, there used to be in, you know, public high -- the public school there used to be clocks that will run every day you hear click, click, click, click, click as they'd reset the clocks to -- I don't remember that -- gives away your age, yeah, click, click, click, click, click and it reset. That's exactly the same thing light does every day -- click, click, click, light resets your biological close so it's exactly 24 hours, number one. But more importantly, number two, it sets it to Colorado time -- sets it to Colorado time. So that's what happens. So when you change time zones, light coming into your retina and some other factors reset your biological clock to the time zone you're in. But it takes some time. So this suprachiasmatic nucleus, this is the master circadian clock in your body and that's a miraculous piece of tissue that I -- my lab has studied for many years. And if you look at a brain slice, a rodent brain slice, if you look at the base of the brain you see these two structures because it's -- actually it's paired nuclei. Each one of these structures, the SCN, contain, you know, 5,000 cells, neurons and many of which can generate this 24-hour rhythms. It's right above the optic chiasm. It's kind of interesting where it's located evolutionarily because it has -- there's a very small fiber that goes called the retinohypothalamic tract that runs from the optic nerve to the suprachiasmatic nuclei to give them light information. And that's a whole fascinating story because it's not even the normal photosensitive cells in your eye that actually -- that provide this information. It's a very intriguing story. But the important part is light gets to 7

8 the SCN via special tract and these SCN then get reset each day, stay exactly at 24 hours, and synchronize to Colorado time which I think I might be partially synchronized to Colorado time now. So these cells in mice can be recorded in culture and can be actually studied in culture. The -- yeah, mice -- the neurons are plated on to plates -- electroplates, and this is work in my lab many years ago by one of my post docs Eric Herzog (phonetic) that shows three neurons from an SCN of a mouse generating electrical activity. So the graphs are a number of impulses. So these are neurons so they go -- if you listen to them on a recorder, if you see the tick, tick, tick, tick, tick as they generate electrical impulses. So it's kind of fascinating. During the day time these cells are ticking away and they're generating 3, for example, in this case every 10 minutes 3,000 spikes, 3,000 impulses. And then during the time that would be night time, these cells are pretty much silent. And then the next day they generate impulses again. So this -- these are cells in isolation, in culture, kept under constant conditions that in each one of these lines represents 24 hours. And I think you can see this in the back? So these -- this is a circadian rhythm. And this is kind of -- when you see this in the lab it's kind of miraculous. This is a neuron, this is a biological clock. It's generating this 24-hour rhythm. It's not exactly 24, right? As I said, it's circadian because there's no light correcting it. And in this case since it's a mouse, mice have periodicity that's a little less than about 23.7 hours. So at every 23.7 hours these cells generate sort of peak activity. At night they're pretty silent -- pretty silent. So here's the bad news for those of us that are over 30 or 40 years old. As you get older -- and this is recent work from our laboratory actually at UCLA -- unfortunately that silence during the night time and these neurons disappears and the neurons become more active at night. So even though they remain active during the daytime generating a lot of impulses, unfortunately they begin to now generate impulses at night as well. So the amplitude of the circadian rhythm begins to decrease. And it reduces -- and it's almost certainly involved in sleep pressure, reduces sleep pressure. And 8

9 that's why, you know, 2:00 o'clock in morning you wake up because your nervous system can't keep you asleep anymore very effectively because your biological clock is decreasing its amplitude. And we've actually recorded long term from behaving mice and old animals and you can see it's dramatic. It's -- and it's depressing -- it's depressing that old animals -- it's not a good sight. I mean here they are, you know, these are middleaged mice we're looking at that and this SCN, the strength of the signal is reduced substantially. So that's another story about aging, I'm not going to get into in any detail but these are young animals and there's young neurons and you see this beautiful circadian rhythm, so. SPEAKER: (Off mike). MR. BLOCK: Round the clock. It's completely -- this is completely indigenous. And that rhythm is being generated by a circuit that's now under sort of molecular circuit and molecular feedback loop involving a number of genes that are called clock genes. You may hear this in the press -- people talking about clock genes. So there's a handful of genes that are involved in generating these 24-hour rhythms not fully understood but partially understood. And the only important thing here is that now that some genes have been identified, the period gene, the cryptochrome gene. And the little bit that's understood about the feedback loop that generates the 24-hour rhythms, now it's possible to actually track the behavior of some of these genes with something called the reporter gene. You can actually take the gene from the firefly, luciferase gene from a firefly you can make a transgenic mouse where the luciferase gene now reports on the activity of one of your clock genes. So when the clock gene becomes active, luciferase is produced in the mouse brain and if you have a presence of luciferin, the substrate, just like a firefly, the brain glows. So the brain will glow rhythmically. And now you can track -- and the important thing here is you now can track molecular rhythms as well as electrical rhythms. And that becomes very important you'll see in a second. Now you can really -- so it's amazing, you can actually from a -- if you shave the fur off of an animal and you have a sensitive enough photometer you can actually 9

10 measure the brain glowing rhythmically. And it's really the SCN that's doing most of the glowing. SCN is quite dramatic. But the other thing that this technology does, this transgenic technology is you can now measure rhythms in other parts of the body beyond the brain. So the brain is the place where you can measure electrical activity from neurons but now you can measure tissues from throughout the body. And here is the new news and "new" being plus 15 years. There's not just one clock. Almost every tissue in your body and many of the cells in your body all have the capability of generating 24-hour rhythms, molecular rhythms. And this is where the whole field begins to change. So first you can see -- I just want to show you what an SCN looks like. This is -- these -- this is photometer measuring the luciferase activity in a brain slice of SCN -- bright during the daytime so as the -- this clock gene is active, quiet during the nighttime. So this is a tissue that you can see is -- I just want to show you -- these are the individual cells, the suprachiasmatic nucleus neuron. So that's following a luciferase, that's light production from luciferase and we're following the circadian rhythm from the SCN. But here is the thing that's so dramatic. If you look at other tissues in the mouse -- and this is almost certain anything in the mouse like this that it's going to be general for all and it's true for all mammals that have been looked at, it's going to certainly be true for humans and it's certainly true of cells in humans where this has been measured -- is that almost all the tissues have circadian rhythms independently -- independently. So if you remove a small portion of kidney and you record its molecular activity, it has a 24-hour rhythm or something. You record it from the lung, the lung has a rhythm. The thymus has a rhythm. The cornea has a rhythm. Your entire body is a clock shop. There are clocks everywhere in your body. There's the central clock, the SCN that's so important because it gets lighted from the light from the retina. But there's a lot of clocks. So what this looks like -- and now you understand circadian disruption better as the following. There are clocks, circadian rhythms in all of your major organs. There's a clock as I said in the SCN -- the clock in the SCN can be viewed as sort of a master clock, the 10

11 controlling clock. It gets light through the eye, gets reset. So it's -- keeps time, it's what sets your time to Colorado time. It then controls all these other clocks and sets their -- help set their time, right? So that's the process. SCN gets reset. So you fly from Japan to L.A. First thing that happens when you start getting light in the morning is your SCN gets reset. And this can happen pretty quickly. Your SCN can get reset pretty quickly if you have bright light and at the right time. But then that SCN has to reset all these other clocks -- that takes time. And some of those clocks are really slow to change -- slow to change. Some of those clocks actually can't even change directly. The SCN can't directly change in your liver -- liver enzymes. The liver is more sensitive to your mealtime than it is to your SCN. So it's your mealtime that's going to set your liver rhythm. So this is already giving you a hint about jetlag and what you have to do if you want to get over jetlag. So mealtime becomes really important. So this is really a complicated system of clocks. It's a clock shop. And the way I try to explain it -- actually when I explain this to students as probably the best model for this to think about is a bunch of pendulums on -- pendulums swinging together -- big, heavy pendulum in the middle, the SCN, all the other tissues are also -- oscillate as their pendulums and are all connected by rubber bands. And these entire system is swinging together, all right, so all the - - so this is synchrony. All your circadian rhythms are in synchrony, you're in -- you're at home, you know, you're in your home, your home territory, you're getting a normal light cycle, you're getting a normal manner of rest and everything is swinging in synchrony. What happens when you change time zones? What happens is your SCN shifts space, that is it moves to a new position, resets the local time. But because these rubber bands are not -- they're not iron bars, they're rubber bands, it takes a long time for all the pendulums to swing together. So after you've changed time zones it can take weeks before all these different rhythms in your body swing together. So what's the -- what happens during jetlag and when you have this malaise? You're waking up in the middle of the night to go to the bathroom because your kidneys are 11

12 still active at the wrong phase. You're hungry at the wrong phase. Liver enzymes are at the wrong phase. You feel terrible. And the problem is you just have to sort of grin and bear it because it's going to take time for this entire system to come back into synchrony. And that synchrony is really important for health and for cognitive performance. So that's the system. That's enough sort of biology -- I mean that's the system - - SCN master oscillator, master clock. All these other tissues are rhythmic. You've got this very complicated temporal system in your body. So it's complicated as your body is in terms of spatial organization. This is -- whole dimension, the temporal organization that has been undervalued until we had the tools to study. And so your whole system is a very sophisticated timing system. So now let's talk about living with that timing -- yes, sir? SPEAKER: (Off mike). MR. BLOCK: Couple weeks -- a few weeks we see. And when -- and this is the scary thing and we see this in rodents when we study this. When you shift this phase of - - let's say you shift the phase of the light equivalent to flying, let's say, eastward for, let's say, 6 hours, there were some tissues that not only don't shift immediately, they stop oscillating. They literally stop oscillating. You know, there is a point called singularity point where some oscillators stop oscillating and it'll take a while for them to even begin oscillating again. So you really are a mess when you change time zones. I mean, it's amazing we can do it as effective as we can because your body is under really extraordinary stress when you do that. And if you are shift worker, rotating shift worker, you're doing exactly the same thing regularly for long portions of your life. So I worry less about jet lag except for flight attendants and, you know, perhaps some pilots but it's more of problems for shift workers and the phenomenon is very similar. So let's talk about living sort of -- living in this high technology world and what's happening to some of the challenges and let's first talk about sleep. Sleep is the most prominent circadian rhythm in human. So your sleep cycle, the timing of your sleep cycle is controlled by your biological clock. 12

13 Sleep itself is a complicated, a very complicated process with a lot of different neural structures involved but the timing of sleep, which is what often is the thing that concerns us most is controlled by your SCN and other - - and mostly by your SCN. So let's talk about sleeping in a normal environment. Normal environment means you're exposed to a light-dark cycle and you are not changing your time zone, you are not doing shift work, not working at night, you're just trying to live a normal life on a normal life cycle. And let's look at some of the challenges. So first, how much sleep do you need? And this has been a big debate and it's hard to estimate. Generally the studies that try to determine how much sleep you need, try to look at how much do you sleep during vacation for example to determine what your natural sleep length is. And it also looks sometimes at how much make-up sleep you have, so in other words if you work -- during the work week, if you are only sleeping eight hours a day and then all of a sudden you sleep ten hours during the week end, you obliviously are shorting yourself during the week day. So there's a lot of different ways to measure it. But the number of -- there have been number of studies on what's the amount of sleep and it's always more than you get probably. And so for adults, it's about 7 to 9 hours. And you know, there is some genetic variation among people, how much they need. So it's 7 to 9 hours. But you know for example school age children, it's really pretty dramatic, 5 to 10 years need 10 to 11 hours. So these are the recommended times when you -- if with this much sleep, most people show no signs of fatigue during the day. So we actually quite a bit -- you need about 7 to 9 hours to be fully restored and not napping, not needing to nap to catch up. So what happens if you don't get enough sleep? And this is probably known to everybody. There's a whole bunch of effects of not getting enough sleep chronically. So chronic sleep loss leads to memory problems, reaction time goes down, reasoning and judgment can be impacted tremendously. Psychiatric disorders, there's a whole host of psychiatric disorders, anxiety disorders that are because you may not be getting enough sleep. 13

14 The reasoning and judgment is really interesting because as you get tired, one of the first things that happens when you get tired is you misestimate how tired you are. And people that are really tired -- and they did this with interns actually, University of Pennsylvania, they couldn't estimate how tired they were and that's really dangerous when you think you are alert. And that's why people drive off the road at the night when they are tired. It's because they actually don't realize they are tired. If you know you're tired, you'll pullover. I mean no one's going to drive if you realize you're falling asleep. You fall asleep before even know it, you think you are alert, you are not alert. So there's some immediate impact obviously on cognitive impairment and a whole bunch of physiological impairment. There is a pretty good evidence now of weight gain, metabolic disorder. It showed a first study in people with obstructive sleep apnea and you often, you have that because many people are overweight and then they gain weight because they have obstructive sleep apnea because not sleep through night. Now there is a lot of studies on sleep duration and weight gain. Cardiovascular endocrine dysfunction, autoimmune disorders, there's actually a lot of data behind all this. There are lot of studies. I was looking through the number studies and mostly this is pretty compelling. I mean -- there is a lot of evidence that short sleep can lead to a whole bunch of ill effects and the argument is sleep hygiene is really important and I guess, you know, maybe it's too late for some of us but I have been working on my children to convince them that it's really important and certainly our students. I remind them, a lot of our students get in trouble because they actually sleep too little. They get anxious and can sleep less and they get this feedback when they're not sleeping and that becomes really the first problem you pick up with some of the young folks. So that's one issue, you know, how much do you need to sleep and what happens if you don't sleep enough. So here is why it's so difficult to get enough sleep for lot of people, is that human sleep varies not only in the duration of sleep. So, you know, this is pretty well genetically said, you know some people need 7 hours and 14

15 some people 9 hours. So we know that, we know people that need more sleep, that's one issue. But the second issue is the phase, the time at which you go to sleep is also has a genetic component and it differs dramatically between people. And we all know this. I mean there are people who we call larks, who 9:00 o'clock they are ready to go to sleep and 6:00 in the morning, they are wide awake and functioning at a high level. There are other people who can't put three words together at 9:00 o'clock in the morning, owls that really need to sleep, need to sleep at a very different phase. So some individual needs wake up early, obviously go to sleep early, often I'm afraid it was larks and some are owls clearly. But what's the distribution? So (inaudible) who is a researcher in Germany stared this huge, I think was a web study where he had people reporting. What he does is he asks people on weekends to keep track of their sleep on weekends and try to figure out when you are not working or when you are on vacation, what time would you go to sleep and what time would you wake up when you not under sort of the stress of and the requirement that being at work at a certain time. So he calls that you are chronotype. So what he does and he has -- thousands of people in Europe have done this, no I think a hundred thousand now is, what you do is you keep track when you go to sleep and so for -- here is an example of an owl. On vacation, we go to sleep in 2:00 a.m. in the morning. Really only gets tired late after mid night, go sleep 2:00 a.m. in the morning, sleeps till 10:00 America, that's an 8-hour sleep time. The mid point is 6:00 a.m. in the morning, right. So he says, well 6:00 a.m., that's 6 hours after midnight, let's call that a chronotype of 6. So that's now a chronotype of 6. You know, a person who goes to sleep at 9:00 o'clock in the evening and wakes up at 3:00 or 4:00 and the morning, that's an early, that's a lark and not might be a chronotype of 2. So then he has the distribution and you can just look at the dark bars, there are two studies here, light bar, dark, but just look at the dark bars. It's kind of interesting, you know, a chronotype of 6, right here, it means you're going to sleep 2:00 in the morning normally. So there is quite a few people on that group of extreme 15

16 owls -- extreme owls. So what's the problem? So those people have to work in society where they have to wake up in the morning with an alarm clock. They are continually sleep deprived. So owls really have a problem in society unless they can, you know, own their own businesses and can come in at 11:00 in the morning, you've got a great deal. If you have to wake you and live by sort of contemporary sort of work standards, you are stuck. So it's very challenging. Even in a normal environment, owls will struggle. Larks have real advantage because you know, you can always sort of control when you go to sleep and there are no -- they are alert in the morning when the alarms clock goes off. So this is chronotypes and this is -- this is interesting. And many of us now worrying these bands measure a sleep and there is a gold minded data out there now on chronotypes. We've just got to get these companies is to free up their data because they got huge amount of data on chronotypes now which is interesting. So what happens if you are late -- if you're an owl, what are some of the problems? So (inaudible) followed some of these folks with questionnaires and you know in terms of depression scale the longer you chronotype, the more delayed you are in going to sleep, the more depressed modes you have, more frequently you tend to consume more caffeinated drinks, which not surprising, you're trying to stay awake. Smoking -- there's some correlation with smoking, and not much with alcohol but some correlation with smoking. But clearly mood is impacted because you are tired all the time, because you are forced to work during the day. So this is even in the normal environment, not shift work, you're still having a challenge just because of the way we operate. I'll just show you some different kinds of sleep cycles because they are interesting to show you in a normal environment. These are people that kept sleep logs of when they went to sleep and when they woke up. So each dark bar represents a day, so this is about a month and the time of sleep is represented by the beginning of the dark bar and the time -- and the wake up time is at the end of the dark bark. And you see -- and these are undergraduates at Harvard initially. Normal -- initially I think the initial 16

17 sleep cycle and you can see an undergraduate at Harvard are going to sleep midnight, this is the 23 years ago, I don't think is change too much, 11:00 o'clock, 11:00 o'clock weekends they party, so they go to sleep late, wake up late. So you can see the weekly rhythm. But that's very typical. No one with that sleep pattern goes to a sleep doctor, that's not a problem. So here is an extreme owl, and there is a name for it, delayed phase sleep syndrome. These are people that go to sleep labs because they are tired all the time. So look what they do on weekends, they go to sleep like 2:00 or 3:00 in the morning and then sleep till 2:00 or 3:00 -- like 1:00 in the afternoon, 2:00 in the afternoon. Extraordinarily. So they're just completely out of sync with society. Look what happens during the work days, they can't go to sleep till 1:00 o'clock, this is midnight. So they can't go to sleep till 1:00 or 2:00 o'clock and the alarms goes off at 6:00. Weekends, look what they are doing, weekdays, they barely sleep 3 or 4 hours everyday during the weekdays. So they try to make it up with these very long sleep-outs on the weekend but they never make it up and they have all the impact of lack of sleep. So this is really problem for people with delayed phase sleep syndrome. There is also people with advanced phase sleep syndrome that go to sleep too early. So there's a family in Utah, and the reason why I mentioned the family in Utah, because they got -- genetics has been done on this family and they've got a mutation in their clock gene, the whole family wants to go to sleep, I think like 6:00 in the evening, 7:00 in the evening, they're all getting tired. The whole family gets tired, so you know they want to go to sleep at 6:00 and they want to wake up at 1:00 in the morning. And it's because one of their genes, one of their period 2 genes has been mutated, and it's kind of fascinating. So some evidence of genetic control over that but this delayed phase syndrome is much more common. Then in the elderly especially there's often fragmented sleep and you can see this -- and I remember my father, when he was in his 90's, would complain that he couldn't sleep at nights and he wasn't. He was doing these little bouts of sleep but also napping during the daytime. 17

18 So this is really the breakdown of the biological clock, the sleep generator and that we can see in rodents. We can see exactly the same thing happen and we can see their brain begin to deteriorate, the neurons that control their rhythm. And then finally there are people who can't synchronize. They actually have a pretty good sleep cycle but it's not stable, you see it's moving and that's true for a lot of people who are blind. They can't synchronize their clock, so their natural period is about, maybe 24 and a half hours. And so they drift, their sleep drifts throughout the month. So that's poor synchronization. This is sort of fragmented sleep, this is probably what's most common, is this delayed sleep, extreme owl. So that's in a normal environment. You know most people again are lucky, they're dealing with a normal sleep cycle but as I said for a lot of people, it's challenging just because the phase of sleep doesn't match well with their work cycle. It's hard to match up your work cycle and your preferred sleep time. So that's easy, that's people living in the normal environment. But technology has made it easier to live in abnormal environments. So what about abnormal environments? People that do shift work, people that fly a lot, flight attendants because they're the ones that appear to be most at risk because they fly a lot more than pilots and all of us that are now getting excessive amount of light at night. So let's just take a look at that. So what's the evidence of the problems of what happens with circadian disruption? I've mentioned some of these before, much the same as sleep loss. You know reduction in vigilance, compromised immune system, increased incidence of Type 2 diabetes, increased evidence of cardiovascular disease, weight gain, increased incidence of breast cancer and reduced longevity in laboratory animals. And the interesting thing here, the only thing that I would point out that is really amazing is a lot of these phenomena are not because of you sleeping less, it is actually a disruption of your circadian system. Sleep loss is an impact of your disruption, but it's disruption per se that has negative health 18

19 consequences. That's important to remember, it's not just that you're not sleeping well, it's the actual disruption of circadian rhythm has profound impact on your well-being. So you know, what are those impacts of people that take advantage of technology? So working at night, now we can work at night and as I mentioned and I showed you this before, your vigilance at night is very low. And this is an experiment Tim Monk, at the University of Pittsburg did an experiment where people had enforced bed rest. So these were people that sit in their beds, lie in their beds and they agreed to do this like 36 hours, so they're kept awake. So you have to stay awake for 36 hours, you just don't move a lot because we don't want fatigue to enter in here. We don't want fatigue from muscular activity enter in, and he has people sort of on a computer screen, checking their vigilance, and sure enough, what happens, you find people. What happens there is a pretty high level of vigilance during in the daytime and it actually gets better in early evening and look what happens at night. Remember they're not sleeping, they're up continuously but look what happens. The drop occurs dramatically right around the time that would be dawn, these people in continuous dim illumination, so there's no external rhythm at all. There's a huge drop and then even though they're still awake, they've been up this entire time, look how vigilance improves again. So the amazing thing is even if you're forced to stay awake for two or three days, you still go through the circadian rhythm in vigilance. It's quite amazing, it decreases steadily but nonetheless, it gets better on the second day again. The real problem is late night when you're really not vigilant. And then there's a whole host of big accidents that have occurred when people lost vigilance at night. Now every one of them have other factors no doubt, you know, that there are things but every one of these big accidents, you know Three Mile Island nuclear meltdown, Chernobyl, released (phonetic) in Bhopal and the grounding of the Exxon Valdez in the end was fatigue and probably circadian phase. These are late night accidents when people were not vigilant. So again, working at night, you can't get away 19

20 from the fact that you have a decrease in performance even if you've slept. Even if you've slept, you're still going to have a decrease in performance at night, so working at night is just hard and you add some complexity, rotating shift work. So what happens, so now we have these rotating 24-hours society, rotating shift work. An early study showing that shift workers reported significant level problems of cardiovascular problems and digestive disease problems, you know largely you know the problems of difficulty discomfort but also you know more serious problems with shift workers and this is an early study. There are huge number of studies on shift workers now, rotating shift workers. All very concerning and most thorough studies have been done with nurses and those are more concerning because of serious sets of diseases. So nurses doing years of shift work report very high levels of problems and in fact in a couple of studies the level of cancer among shift workers is high enough that the World Health Organization deemed it a carcinogen in 2007, shift work as a carcinogen. Now there is a lot of debate about that because there is always confounding factors. But there are some remarkable studies of Finnish flight attendants and they're looking at their jetlag not shift work but jetlag and it's pretty convincing, the number of time zones you change really is a function on the incidence of -- in that case it was breast cancer, but other kinds of cancers as well. So clearly rotating shift work is an enormous challenge and again rotating shift work causes circadian disruption, because if you look at people's circadian rhythms when you're shifting every week or every two weeks you never catch up, you never catch up. So there is always a problem, your constant circadian disruption. So just think about what's going on your body your SCN may shift but other parts of your body are not shifting so you're always at a disadvantage. Years ago, when I was running a center we looked at Bethlehem's field, we looked at shift workers actually. Now it's kind of fascinating, we looked at accident rates of shift workers and it was amazing. Every time you shifted to new time -- work time, 20

21 there'd be accidents, there'd be increase in accidents, was pretty dramatic until about two weeks when you began to adjust, the accident rates went down. So this is really challenging, so again sort of a modern innovation rotating shift work has a very negative consequence on health. Okay, what about transmeridan flights, so probably very few of you are rotating shift workers, but a lot you fly a lot I bet, and so what's the issue about with the difficulty in flying across time zones? So we know right away it takes a long time to readjust when you change time zones, and for most of us this is just an inconvenience. But when people are giving questionnaires about when they're sleeping regularly, eating regularly, and feel decent again, when you do questionnaires it's clear that it takes good deal of time and it's a kind of fascinating because west bound if you are flying west remember this is only true for up to about 9 hours because at 12 hours, it doesn't matter whether you go east or west, it's the same shift but up to about 9 hours west bound flight, it takes you know, I believe in 8 or 9 days most people report you're completely resynchronized. In most people it's much sooner. You know, you can see within 3, 4, 5, days people are sleeping normally. East bound is much harder, so east bound flight, flying towards the sun or advancing your biological clock is much harder and it's true for the animals on a running wheel if you switch the light schedule it's dramatic. The difference of an advance and the delay of your clock, so advancing your clock, some people even 18 days out, it took 18 days before they felt normal again. So, shifting really does put stresses on your system and this has been studied again showing up in flight attendants. There are some real health consequences to it, for most of us it's not too much of a problem. But it can be serious in the elderly at least when it gets to mice. So I have to show this study we did few years ago that shows you how dangerous jet lag can be, at least if you're a mouse, so these were -- and I will tell you the story, it's kind of interesting how it came about. We were studying old rats, and we were just looking out how quickly their circadian systems could adjust and we, one of my post docs Shin Yamazaki in the lab, came in the morning and said, you know, so Gene this is really incredible. 21

22 "You know, I have six 6 animals, old rats these were 2-year old rats, 6 animals that I delayed the light schedule by 6 hours, so that's like flying from New York to Paris and another 6 animals, I advanced the light schedule, sorry -- delayed, so it was like flying to Hawaii from New York. And another six animals, I advanced the light schedule like flying to Paris and I came in the morning and three of the animals were dead. Three of the animals were dead but only the ones who were advanced flying east ward, none of the west ward." And I said Shin, I said you know, check the water, make sure we are not in trouble here, make sure the animal had plenty of food and I'm thinking immediately, we're going to be in trouble with the animal protocols. And he comes back and says "No, no everything's fine, the animals had access to water, had access the food they are dead, something happened." And then I said, Shin these are 2-year-old animals, we just had this unusual situation where three animals died. Just 2-year-old mice, I mean 2-year-old rats will die. I mean it just happens. So Shin said "No, no." But I put it on the shelf, the data. I came back a couple of years later when I had a little extra money and I brought mice that had been reared identically for two years almost two years from the National Institutes of Aging. So I got these wonderful but very expensive mice. And these mice are old enough that they'll die, I mean these are animals near the end of their life. So every month you are going to lose some animals, because you know that's getting pretty old. But it was really dramatic so I'll tell you the experiment we did. We took 32 animals in each group, it was a big experiment 32 animals we just kept on a light-dark cycle, 12 hours of light and 12 hours of dark just maintain them and if you do that and you measure how many animals are still alive after one week, two weeks, three weeks, four weeks. You know even with the animals that are just on a normal light schedule, some die so after you know, after 8 weeks you know we only had been 90% of the animals left. So 10% of the animals died naturally just because they were old mice right? Then with another group of animals 32 animals, every week we advanced their light schedule by 6 hours so it's like flying from New York to Paris waiting a week and 22

23 then flying further east you know 6 times zones and doing that routinely. And in another group we did west ward travel. You know, fly to Hawaii and keep flying to Asia. And it was dramatic with -- and so this was redoing with the rat data. Now with the real experiment, a controlled experiment. And sure enough the mice that were going east ward, by the end of the 8 shifts in the light schedule, there is only 43% living. It was killing animals every time we changed the light schedule, animals would die. Hard to believe, we redid the experiment several times, reproducible. We then said "Well shifting the light schedule every 6 to 7 days is bad what happens if we shift the light schedule every 4 days, so that their circadian system never catches up, it's constantly trying to catch up and it was even more dramatic. So this was animals that we shifted every four days, old mice again, interesting if you went westward, you know, we lost some animals but not many but every 4 days if you shifted the light schedule in advancing the direction, animals would die until, by the end of the experiment we were down to about 50% of the animals still alive. So these are old mice, they are going to die within 3 to 4 months almost every one of them are going to die so it's not the question of a young animal. In fact it doesn't happen with the young animals. But it does tell you that something about shifting your biological clock is stressful, and it's especially stressful as you get older and probably these animals are equivalent to 90-year-old humans. So very few 90-year-old humans are flying across the globe, some are but not very many. But a lot of 90-year-old humans are obviously dealing with day light savings time, where they have to change the biological clock in the difficult way actually when we change the -- to daylight savings time. They're living in institutional housing where the lighting isn't very good and they are not getting very good light signals. Sometimes they're in hospitals in continuous light because in fact they were being taken care in environments where it's never dark. So it's relevant to humans it's not, I think jetlag itself at this age is not really a relevant phenomenon, but the fact that human circadian systems, mammalian circadian systems are frail as you get older is something we do have to pay attention to 23

24 but for different reasons, probably for how we take care of the elderly. So let me finish up, I am going probably too long here. Let me just finish up with the last thing, light at night which affects all of us. So light pollution, if you look at the light and these -- everybody has seen satellite maps of the world and United States in this case, from the late '50s to 2012, it's extraordinary how much more light we're generating. You know, we are generating more light, we're generating more white light. And the only reason I said white light, is because this blue white light is the light that most impacts your circadian system, but it's extraordinary how much light increase there is in the whole world but especially in the U.S. So that's fact number one, fact number two we all know is that weight gain in this country is just spectacular. And I'm sorry, it's hard to see here but you know, if you look back in 1985, there were a few states where the incidence of obesity -- I think obesity defined here is 30 pounds, if you're 5'4", 30 pounds over average weight and even in some states, I think I think it was 15 to 20% of the people, 15% being obese. There were some states, most states were very low levels. And now you have levels greater than 30% in a whole host of states. So, it's just extraordinary, the increase and it's a concern. And increasingly, you know, obesity is linked to whole set of you know behavioral patterns but increasingly we are becoming concerned about the effect of circadian disruption, specifically light at night on weight gain. So it turns out, you know, if you look at what happens with light at night, there's two things that happen if you have light at night, it disrupts your _circadian rhythm, so if you take animals and you place them in continuous light, their rhythms actually are disrupted. If you place animals in a normal day light and then just keep dim light at night amazingly it damps their clock genes, all these rhythms I showed you, clock genes those are all damped. Even a little bit of light at night damps it and it does two things, it damps the circadian rhythm, light at night and it also disrupts endocrine signaling. So for example, as I said it'll suppress melatonin levels and can actually drive melatonin levels 24