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A Spotlight On: Sleep Deprivation & Genomic Regulation – Derk-Jan Dijk

We speak to Derk-Jan Dijk, Professor of Sleep and Physiology at the University of Surrey, Director of the Surrey Sleep Research Center, and member of the Care Research and Technology Centre of the UK Dementia Research Institute.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello! and welcome back to the latest “A Spotlight On” interview. Today I’m joined by Derk-Jan Dijk, Professor of Sleep and Physiology at the University of Surrey, Director of the Surrey Sleep Research Center and a member of the Care Research  and Technology Centre of the UK Dementia Research Institute. So Derk-Jan, would you be able to introduce yourself and give us a little overview of your work?

Derk-Jan: Yes, sure. I’m a biologist by training. Many, many years ago, I studied biology in the Netherlands. I then completed a PhD in medical sciences, which was focused on sleep and circadian rhythms in humans. After that I went to several places – Switzerland, the United States… and came to England back in 1999. Now, I’m still here in England and I’m still doing research on human sleep and circadian rhythms!

Of course, when you’re studying sleep and circadian rhythms in humans, you can study many different aspects – you can study sleep physiology, how much deep sleep you get, how much REM sleep you get. You can study the effects of not sleeping enough – How well can you think or remember things after a poor night’s sleep? Does your mood change? Do you become grumpy if you don’t sleep enough? But another thing you can do is study what happens with the human transcriptome – what happens to it if you don’t sleep enough, how does gene expression or the abundance of transcripts change with the time of day? These are some of the questions we have been working on for the past 10-15 years or so.

FLG: That’s really interesting. So, why is sleep so important?

Derk-Jan: Well, it’s a good question. Often, you get the answer that we spend around 1/3 of our lives sleeping, so it must be important. I think that’s a fair enough argument. Another answer you can give is that if you don’t sleep, you don’t feel well. So, there must be something happening during wakefulness that needs to be restored or recovered or repaired during sleep. And you can study the effects of not sleeping enough in different ways. You can look at experimental sleep deprivation studies, where you bring people to the lab and keep them awake for a day and see how they change. Or alternatively, you can start looking at the epidemiology – what happens if people in surveys tell you that they only sleep six hours or five hours and you also have information on their health status? If you take that particular approach, you will find that there are many health associations to do with insufficient sleep.

One association of not getting enough sleep is there is an increased risk of obesity, especially in young people. If you sleep very little, then there is an increased risk of cardiovascular disease. Also, in long term follow up studies (and these are studies conducted by others – for example, The WhiteHall Study) you can see that if you don’t sleep enough, you may have a 20 to 30% increased risk of dementia or Alzheimer’s. So there are these clear health consequences. Other consequences are, well, if you don’t get enough sleep or you have a sleep disorder, you will be fatigued. When you drive at night and you haven’t slept, there is an increased risk of being involved in an accident. shiftwork is associated with disrupted sleep. It’s also associated with disrupted circadian rhythms. And of course we know that shift work is associated with negative health outcomes and higher risk for accidents at work.

So, there are many reasons why it is important to study sleep. The big question is, whether it is insufficient sleep, disturbed sleep, sleep disorders or circadian rhythm disorders – what are the mechanisms linking those aspects of behavior to these negative health outcomes? And if you were to understand those mechanisms or those links, you can understand the function better.

FLG: So how are you researching these mechanisms? For example, is there a physiological signature of a good night’s sleep that you can use as a reference in your studies?

Derk-Jan: Another important question, and you would think that sleep researchers had figured that out. Actually, it’s not so easy. Many of us have experienced waking up in the morning and knowing whether we had a good night’s sleep or not. But what is a “good night’s sleep” from the self-report perspective, or the subjective perspective? We do know that if you wake up frequently at night, people will think that that’s a bad night’s sleep. We also know that frequent sleep interruptions are, from a physiological perspective, not good – you can objectively measure that the next day, people will not perform as well as after a night that was characterized by continuous sleep. So, sleep continuity is certainly one aspect.

There are other aspects to sleep – deep sleep or slow wave sleep – that many people feel are very important. And I can give you the reasons for that view later. But yes, we do find some correlations. We do know, for example, that deep sleep is very much reduced with aging. Of course, there is cognitive decline with aging. So maybe slow wave sleep is important. In our own research, we also find that rapid eye movement sleep (so that’s the sleep stage during which we dream a lot) is important. When we do cross sectional studies, refined associations, we find that more REM sleep is good. So, these are some of the aspects, but it is too difficult to simply say, this is a good night’s sleep. And for these reasons, I think we can’t really make that particular statement. We’re still working on it.

FLG: Hopefully in the future we’ll see some developments here.

Derk-Jan: Hopefully. But there is another thing that’s interesting… you may think that, okay, I can understand that short sleep is not good. But if you look at the literature and the immunology, you can also find evidence that long sleep is a predictor of negative health outcomes. So, when you’re sleeping nine hours or 10 hours or more, that basically isn’t a very good sign. And you can come up with explanations for that. If you’re sleeping that long, you may already have some condition. So, when somebody tells you “I sleep nine and a half hours every night and I take a two hour nap as well” especially when you’re a little bit older, it is not necessarily a good thing. On the contrary, there is probably something going on with that person in terms of health.

FLG: So there’s a there’s a good spot in the middle?

Derk-Jan: Exactly, yeah. Around 7.5 hours. But when you are younger, you may very well sleep more than 7.5 hours. There are also differences between women and men. Women sleep on average a little bit longer, not by much. And so yes, the age is a very important determinant of how much sleep people need.

FLG: You mentioned differences between men and women. Is there a difference in the circadian rhythms of men and women as well?

Derk-Jan: Yes, there are differences. People in Boston did find out that the circadian clock of women runs slightly faster. It’s not by much, I think it was six minutes if I remember correctly, but that can make a difference. If your clock runs faster, you tend to have an earlier clock. So women in general are slightly more morning-type than men. So that’s one difference we investigated here in Surrey – so we looked at what happens if we keep men and women awake, so that now they have to perform during the night, or reschedule their sleep. And what we found (that we published a couple of years ago) was that women are more affected by having to perform at night than men – they self-reported work problems and also in terms of objective measures of performance. We could also see that they were more affected by what we call misalignment between the sleep/wake cycle and the circadian system. As if the circadian system is stronger in women in that way, at night, one should be asleep and not awake. If you are awake at night, you will be struggling. Both men and women struggle at night, women slightly more than men.

FLG: Are there any other groups that are maybe more impacted by a bad night’s sleep than others?

Derk-Jan: If you look at the effect of sleep loss on cognitive function, you will find that young people are more affected than older people. For older people, it’s easier to stay awake throughout the night, if they’re healthy. And that’s very important, because it results in young people needing more sleep, so having a higher sleep pressure. If they have to be awake at night, they will struggle more. And that’s also reflected in epidemiology. If you look at accidents, driving accidents at night, younger drivers are much more at risk our of all the drivers. And we think that that’s not related to experience, or other behavioral factors, we really think that is related to that need for sleep. And of course, you know, when you come to think about it, take an infant or a baby asleep, you can pick them up, and they will just continue sleeping, and they can sleep all the time. You know, by contrast, when you’re older, it’s much easier to wake somebody up from sleep. And all of that probably relates to sleep being less deep as you grow older, which probably is related to an age-related reduction in the need for sleep.

FLG: Okay, and is the decline in how much deep sleep you get as you age related to cognition?

Derk-Jan: There are some studies that suggest that it is and some of our own data suggests that the decline in deep sleep, or slow wave sleep, especially if you decline more than expected for your age, is related to “cognitive slowing.” Like if you have to do some kind of test that requires you to do things relatively fast. For example, one test is what’s referred to as a digit substitution task. You see that all older people start to slow down. But if you have less slow wave sleep, you slow down even more. And so that’s one example. Other people have reported between REM sleep and executive function. So yes, there are these associations and the age-related reduction in aspects of sleep is certainly of great interest also in the context of aging, cognitive decline, very rapid cognitive decline, as you may see in dementia.

FLG: And are we aware of any of the mechanisms that link poor sleep or disrupted sleep with cognitive decline? Or is that still another question for the future?

Derk-Jan: There are several different ways of thinking about this. If you think about memory and memory consolidation, there are certain models of how sleep and memory consolidation interact. And there is a theory called systems consolidation, where memories have been made permanent as it were in cortical areas rather than in hippocampal areas. And certain aspects of slow wave sleep like slow waves and sleep spindles would play a very important role there. Other investigators have introduced the concept of synaptic homeostasis, and this links sleep to plasticity, and also the consolidation of plasticity changes that have taken place during waking. And one quite prominent theory states that well, you can have all this plasticity and all the synapses become stronger and stronger because of the experience you have during the day. But at one point, of course, there isn’t enough space in your brain for all those synapses. And all the synapses and maintaining them is also very expensive, from an energetic perspective. So, you need to come up with a mechanism to maintain the average level of synaptic weight constant. And sleep could play a role there.

So, these are some of the ideas, but you know, sleep is not just about cognition. It’s also about mood and affect and the regulation of emotions, the regulation of experiences, incorporating recent emotional events into the complex memory you have of all the wonderful things (or not so wonderful things) that happened in your life, and sleep may play a role there as well.

FLG: You mentioned the links between sleep and obesity or dementia. Is there much research into the effects of sleep on mental health? I know you’ve just mentioned mood, but would you categorize mood as something separate from mental health?

Derk-Jan: Not necessarily, you’re absolutely right in mentioning mental health, it is very obvious (and it has been very clear for many decades) that most mental health problems and disorders are associated with sleep disturbances. In fact, one of the best predictors of mental health problems are sleep disturbances and sleep disturbances can occur many years before things like depression happen. And if you look at some of the mental health disorders that are associated with insomnia, you can definitely find some quite impressive numbers. So disturbed sleep is an indicator of your brain or your mind struggling to cope with the situation you are in or the situation you are experiencing.

FLG: Yeah, that’s really interesting. And going back to actually measuring quality of sleep. Are there any biomarkers of sleep or specific chemical messages you potentially look for when you’re studying sleep?

Derk-Jan: Sure. Well, first of all, if you want to measure sleep, the first approach is asking people how’s the quality of your sleep? Okay, that’s not a bad start. The next thing you can do is look at electrophysiological markers of sleep, and basically record the electroencephalogram, and you can then look at the various sleep stages; slow wave sleep, REM sleep, sleep spindles, and the continuity of sleep. You can also look at endocrine correlates of sleep – for example, we will see (and this has been known for many decades) that growth hormone is released at the beginning of sleep, especially in deep sleep. And if your sleep is disrupted, as can be the case in disorders like sleep apnea, that initial surge in growth hormone will be reduced. Then there is the good old hormone, melatonin. And we know that melatonin levels are high at night, of course, as it’s released by the pineal and it’s under control of the suprachiasmatic nucleus, but also light and reductions in the amplitude of the melatonin rhythm have been reported to be associated with age-related reductions in sleep.

In terms of looking for other markers, we have done experiments where we experimentally reduce sleep and compare people getting 6 hours of sleep to those asleep for 10 hours. You can then take blood samples and look at how the transcriptome changes – you actually find changes in response to one week of insufficient sleep. And importantly, you can take these blood samples while people are awake. So if you now see changes in the transcriptome, that means that the transcriptome has some kind of a memory of that week of insufficient sleep. If you do this, you find changes in something like 700 transcripts or genes related to these transcripts. And they may be upregulated or downregulated. And if you then look at the kind of transcripts or genes that are changed, you find that some of them are actually related to circadian rhythms. You also find changes that are related to immune function – things like interleukins , or oxidative stress. And these are changes that happen in response to insufficient sleep. Although this tells you something, I’m not necessarily sure that tells you what the function of sleep is. But it does tell you that insufficient sleep has consequences at the level of the of the transcriptome.

You can also take a blood sample from somebody who has been awake for an entire night versus somebody who has a normal night of sleep and do a microarray or similar. If you give the samples to a machine learning algorithm and ask the machine whether it can distinguish between the blood sample taken from a person who has slept or a person who hasn’t slept, it can come up with a set of transcripts that very reliably predicts whether you slept the previous night, even though it hasn’t seen a sample from you before. So that means that there are these changes or “signatures.”

You also may think okay, what about circadian rhythms? We do know, depending on the statistical power, that around 10% of the transcriptome is under circadian control or has a circadian component. The question is, can you take one blood sample, and on the basis of that blood sample, tell the time it is in your brain? Normally, if you want to know what time it is in your biological clock, you would take a time series of blood samples, and then measure, for example, melatonin. And if you if you have a melatonin curve, you can say, Okay, in this person, melatonin starts to rise at 10 o’clock at night, that’s about normal. Now you have a person with a sleep disorder, like delayed sleep/wake phase, in this late sleeper, melatonin doesn’t start rising until two o’clock or three o’clock in the morning, no wonder that a person sleeps late. But to do this, you need to have a time series of blood samples. So that’s labor intensive.

One of the things we did is ask; if you have a multivariate kind of dataset, like the transcriptome, can you, on the basis of just one sample, come up with a time signature? Is there a signature for 10pm? Is there a signature for 11pm? And we have been working on that, and others have been working on that as well. And now there are these one or two sample-based biomarkers of circadian time. At the Festival of Genomics & Biodata we are trying to make people aware of some of the opportunities of doing research in humans, especially if you take behaviors such as sleep into account, or take processes such as circadian rhythms into account. One of the very nice things about humans is that it’s easy to take samples within the same individual. We do our work based on the blood transcriptome. Of course, there’s a lot of animal work, rodent work with brains and livers… But in humans, we don’t have access to brains and livers that easily. That’s why we base our work on what we can measure in blood.

FLG: Yeah, that’s great. And hopefully, these technological advancements will really help answer some of the unsolved questions. Thank you so much for telling us all about your work. I’m looking forward to hearing more about it at the festival as well. So just to wrap things up, could you tell us why you’re looking forward to the festival?

Derk-Jan: I see that there are quite a few people there. I’m looking forward to the opportunity to present the work we’ve been doing here at Surrey to this particular audience. I’m not sure how aware people are of the work we’re doing in humans. It’s a bit ‘niche’, I guess. And it’s not that we are necessarily at the forefront of technologies to look at regulation of the genome or transcription and translation. But what we are doing is applying some of these technologies and opportunities in a unique setting – studying humans over longer periods of time, 24 hour rhythms, which I think is unique, and I hope that people will be interested in some of the work we’re doing.

FLG: Yeah, I’m sure there’s lots of exciting stuff we’ve got in store so it should be a great event.

Derk-Jan: Yes, I’m looking forward to it.

*Derk-jan will be speaking about his work at The Festival of Genomics & Biodata 2023. To see the full agenda and register for a ticket, head to our website.

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