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Experience Life | Can you explain in layman’s terms why your findings are important?

Jonathan Cedernaes | All cells are run according to “clocks” that determine at what time of the day or night cells should be active. These biological clocks basically run key “programs” of our cells, by determining when certain genes, or gene programs, if you like (for example, programs for processing food or repairing DNA), should be run throughout our 24-hour days. Some processes have during evolution been programmed to run during the night (for example, probably DNA repair) and other processes during the day (for example, those that help us process food that the body is expecting us to eat).

These biological clocks have to run in sync with each other, as various tissues are responsible for carrying out different functions in our bodies, and these functions work in concert with each (our organs do not function only as solitary organs, but rather, they also all have different functions that require the function of other organs to allow each specific organ to work optimally). So these clocks are orchestrated by various exogenous factors, of which two key factors are light and food intake. Light affects the central pacemaker (the “master clock”), which is located in a small area at the base of the brain and is called the suprachiasmatic nucleus. This in turn regulates how the other tissues’ clocks work, by affecting a conserved set of core central clock genes (and in that way also their proteins) that are the basic molecular components of each cell’s biological clock.

Animal studies have previously suggested that when such genes are disrupted, or when animals undergo conditions that mimic jet lag (and acute jet lag is sort of what we have implemented in our recent study), the different biological clocks in these tissues become desynchronized. This has been associated with metabolic pathologies. So our findings argue that this could occur in humans too when we experience jet lag.

Furthermore, our genes’ activities depend on chemical marks that surround our genes. These marks (e.g., methyl groups) can be added or removed in certain regions (methylation and demethylation, respectively) to change the activity of the genes. Previous studies have shown that factors such as changes in diet or acute or chronic exercise can change these marks, and that they may be associated with changes in how our metabolism works, by changing how active our genes are.

However, even though sleep loss has been shown to alter many metabolic parameters (for example, increasing insulin resistance), and over longer periods chronic sleep loss is associated with increased risk of type 2 diabetes, no previous study had investigated whether sleep loss could possibly lead to such epigenetic changes by changing the methylation status of genes.

We provide evidence that sleep loss does alter this epigenetic profile of genes, and thereby provide a possible explanation for why sleep loss may lead to more long-term metabolic consequences. This may, however, occur only if one experiences severe sleep loss over a longer period, or if acute sleep loss is experienced on a reoccurring basis.

It is also possible that acute sleep loss can lead to some more long-lasting changes by producing epigenetic changes that are not restored even after a single night of recovery sleep, but this we did not study. That we observed these epigenetic changes for clock genes is however very interesting, as these genes regulate the activity of at least 5 to 10 percent of all other genes in probably most of the tissues throughout the human body. So if these changes are persistent, the changes to these important clock genes’ activity could alter metabolism for longer periods of time, as these clock genes are known to be important regulators of metabolism, which is tied to the 24-hour rhythms that these genes determine.

In other words, our cells are governed by biological clocks which are based on gene activity, and the activity of these genes are in part determined by chemical marks, such as by methylation, through a mechanism called epigenetics. These clocks have been found to be important for normal metabolism, and animals that lack these clocks have impaired insulin sensitivity, and can develop obesity and type 2 diabetes. We found that two tissues that are important for handling blood glucose — which is essential to keep tightly regulated to avoid type 2 diabetes, which sleep loss has been linked to — are altered following one night of sleep loss. The genes’ activities were altered, but also the regulation of these genes — their methylation levels. This combined set of changes could be an explanation for why sleep loss can lead to glucose intolerance — which we observed in our study — and type 2 diabetes, which others have linked to sleep loss.

In addition, the fact that sleep loss can produce epigenetic changes provides a novel mechanism for explaining how sleep loss can produce more long-lasting changes, perhaps especially to metabolism, as we observed that such changes affected the clock genes, which regulate our metabolic “programs” and determine when they will run during our 24-hour days of sleep and wakefulness.

EL | Why is it important that the tissues’ clocks be synchronous?

JC | The body has not evolved so that each organ is a solitary organ without communication with anything outside of this organ. Rather, the tissues interact with each other and they depend on each other. For example, a lot of the energy that we use throughout the day either comes from the liver or from adipose tissue, and at times of the day when this need is greater, you want the body to be programmed so that this greater need is met without having to conflict with other processes that might require greater energy at other times of the day.

Secondly, you want the same synchrony within each tissue as you, in most cases, want the entire tissue to function in the same way at the same time of the day. Otherwise, some cells might be doing one activity at a time of day when other cells in an organ are doing something different, and this could interfere with each other and the combined functional output of a given tissue. This synchrony is also fine-tuned by the external environment, for example by light, so that the body can be “reprogrammed” to anticipate when it will be active and require certain processes to be going on, and vice versa, when it will be inactive (most likely, sleeping) and then switch on other processes.

EL | How did the night of sleep loss negatively affect participants’ metabolisms? Did all participants see similar effects?

JC | We utilized a glucose-tolerance test to assess the participants’ glucose handling — basically a test of their insulin sensitivity. When glucose is ingested, the body, or pancreas more specifically, responds by secreting insulin, which tells tissues in the body to take up glucose so that levels in the blood are not too high — this could otherwise be harmful and occurs in diabetes. So glucose tolerance tests, where participants usually drink a standardized amount of glucose dissolved in water, are used around the world to assess individuals’ glucose handling as a measure of their insulin sensitivity (although this can be measured in more complex manners than this, you can say that the oral glucose tolerance test, or OGTT, is a simple and readily available measurement of this).

We let participants ingest 75 grams of glucose dissolved in water and measured glucose values before this glucose ingestion and two hours later (standardized time points). After sleep, the two-hour glucose values were normal, but after the sleep-loss condition the participants’ glucose values were at the level where one has an increased risk to develop diabetes (prediabetic stage), called impaired glucose tolerance (7.8 mmol/l).

In other words, after one night of sleep loss, healthy individuals displayed glucose values that in the long term (if repeated or if kept at that level for longer periods, perhaps through chronic repeated sleep deprivation or overnight wakefulness as in shift work) would confer an increased risk of developing type 2 diabetes.

There were individual variations in how the participants responded, as there always are, with some responding more in the negative direction and some responding less in the negative direction after sleep loss versus normal sleep. This may be due to genetics, general activity levels, chronotype, and/or dietary habits. However, as we kept the diets, energy intake, and physical activity levels standardized during the study, these may therefore reflect individual characteristics that participants “took with them” into the study. Other studies have for example shown that there are genetic variants in clock genes that confer a greater or lower risk to develop various metabolic phenotypes or diseases, and it is certainly possible that participants that are more protected against sleep loss harbor certain genetic variants that make them more resistant to metabolically detrimental effects resulting from losing sleep.

EL | Your study was focused on healthy, normal-weight men. Do you think you would have had different findings if your subjects had been chronically sleep-deprived? Or unhealthy? Or under- or overweight? Or women?

JC | We chose to study only men to minimize the number of factors that can produce inter-individual differences. Nevertheless, given these facts, it is likely that what we observed might be different in females, older, or diseased individuals.

Chronic sleep deprivation may also produce a different response than acute sleep deprivation. The reason why this would probably be the case is that differences in the effects of one versus several nights of sleep loss have been noted for a lot of other metabolic outcomes that have been studied after sleep loss, and there may also be some adaptation to an acute stressor such as sleep loss over time.

EL | For your study, the participants slept for over eight hours. I know that’s considered “healthy,” but I’m not sure how “usual” it is since many American don’t even get eight hours, let alone more.

JC | You are right that many Americans do not sleep as long as eight hours. In fact, recent studies have shown that sleep duration has declined over the recent decades, at least until 2004; after that the duration may have stabilized. However, today, around 30 percent of adult Americans sleep six hours or less, and 50 percent of adult individuals often report getting insufficient sleep on workdays.

The reasons people are sleeping fewer than eight hours are complex, but may involve job demands and stress, access to technology (smartphones, television, computer games), and societal norms and expectations, but that does not also mean that this is now the “best sleep duration.” In fact, studies have repeatedly shown that seven to eight hours in most cases is the sleep duration that confers the lowest risk to develop many conditions that have been associated with differences in sleep duration (e.g., type 2 diabetes, obesity, cardiovascular disease, overall mortality). Also, as noted above, sleep duration has declined over the last couple of decades, such that the “optimal” sleep duration with great certainty still is around seven to nine hours per night for adults, which also lies within the recommended duration according to the Centers for Disease Control and Prevention and the National Sleep Foundation.

To study sleep loss, one has to have a baseline or control setting that is as optimal as possible for health, so that one can be sure that the comparator, i.e., our sleep-loss intervention, is compared against a good control, which as argued above, 8.5 hours of sleep opportunity should represent. If one would use six hours of sleep as a control, this could perhaps lead to much less of a difference compared with the sleep-loss condition, as six hours of sleep per night already is not quite enough for a lot of people. As such, our findings are highly relevant as they show that compared with an optimal sleep opportunity, one night of sleep loss leads to significant changes in the parameters that we measured.

EL | What exactly would you advise people to do in light of your findings?

JC | First of all, it is important to note that all individuals do not need the same amount of sleep per night. Instead, there are large individual differences in the amount of sleep that you need. I think that one should not be afraid of losing a single night of sleep if it doesn’t happen on a regular basis. A lot of people go through longer periods when they do not sleep the recommended amount, and they are totally fine and most likely do not suffer long-term consequences as a result of having slept poorly for a restricted period of time, as long as their overall and long-term sleep habits are good.

There are also a lot of other variables to consider for general health and the risk of developing conditions such as type 2 diabetes. These include a healthy diet and being physically active. If you are suffering from sleep loss, it is important to try to find the time to recover as much sleep as possible, and in the long run to try to maintain good sleep habits. This means on average, to the greatest extent possible, getting adequate amounts of sleep that each night takes place around the same time. A lot of people think that they can go for short sleep on a daily basis, but they would probably be feeling even better if they were sleeping longer, if they have a greater sleep need than what they are usually sleeping each night.

If you have chronic problems in falling or staying asleep, or if you do not feel rested after having slept even a full night, it is, of course, always advisable to see your physician, who might recommend additional investigations to determine whether any further action is needed.

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