Bone-tired? How about ‘gene-tired’?


New studies show the physiological consequences of not getting enough sleep. (Bigstock/Bigstock)
March 4, 2013

Hey, you, yawning in your cubicle at 2 in the afternoon. Your genes feel it, too.

A new study, paid for by the U.S. Air Force but relevant for anyone with a small child, a large prostate or a lot on the mind, is helping illuminate what’s happening at the genetic level when we don’t get enough sleep.

It turns out that chronic sleep deprivation — in this experiment, less than six hours a night for a week — changes the activity of about 700 genes, which is roughly 3 percent of all we carry.

About one-third of the affected genes are ramped up when we go with insufficient sleep night after night. The other two-thirds are partially suppressed. Hundreds of “circadian genes” whose activity rises and falls each day abruptly lose their rhythm.

Among the genes disturbed by sleep deprivation are ones involved in metabolism, immunity, inflammation, hormone response, the expression of other genes and the organization of material called chromatin on chromosomes. These changes may help explain how inadequate sleep alters attention and thinking and raises the risk for illnesses such as diabetes and coronary heart disease.

“The findings will identify some of the pathways linking insufficient sleep and negative health outcomes,” said Derk-Jan Dijk, a physiologist at the University of Surrey in England, who led the study. “But how these things ultimately lead to obesity or diabetes is an unanswered question at this moment in time.”

The experiment’s results are “consistent with what we know from animal studies,” said James Krueger, a sleep researcher at Washington State University. “But until you do it in a human, you don’t know. We now have a survey of what genes are affected in humans by chronic sleep loss.”

Effects of sleeplessness

What’s clear is that inadequate sleep is a big problem.

In the federal government’s periodic National Health and Nutrition Examination Survey (NHANES), 37 percent of adults in 2008 reported “inadequate sleep” and 29 percent “severe sleep deprivation.” In a different survey in 2010, about 30 percent of employed adults reported sleeping six hours or less each day. Among night-shift workers, the prevalence of “short sleep” was 44 percent — and in those in warehousing and transportation, it was 70 percent.

A two-decade study of Wisconsin parents published last month found that 41 percent of parents of children younger than 18 slept for less than seven hours each night, and eight percent less than six hours. Only 31 percent of American high school students sleep eight hours on an average school night.

Sleeplessness has big consequences, too. The biggest is that it makes people . . . sleepy.

“We have looked at the behavioral response to this kind of manipulation [sleep deprivation] in great detail,” Dijk said. “Sustained attention, reaction time, working memory — we see effects on all of them.”

Cognitive performance, however, is just the most predictable and immediate problem. Others are rare or take years to develop.

Short duration of sleep is associated with a higher risk of developing heart disease and stroke. People sleeping less than six hours a day are twice as likely to have Type 2 diabetes as people sleeping eight hours. Dozens of studies across many countries have found a relationship between short sleep duration and obesity.

People who sleep less than seven hours a night have a slightly higher risk of dying prematurely. (Interestingly, for people sleeping more than nine hours a night, the increase in risk is higher.) At least 2.5 percent of fatal car crashes involve “drowsy driving” — and some experts believe the real number is 10 times higher.

For most of these health effects, the question of whether sleep deprivation causes the problem or is merely associated with it isn’t known. The gene survey may help provide answers.

Not allowed to nod off

The Surrey experiment, whose results appear in the Proceedings of the National Academy of Sciences, examined two types of sleep deprivation, acute and chronic. The latter is harder to study.

“There are 50 experiments on total sleep deprivation for every one on partial sleep deprivation — not getting a full night’s sleep,” said David Dinges, head of the Human Sleep and Chronobiology Laboratory at the University of Pennsylvania’s medical school. “They are in­cred­ibly onerous, labor-intensive and difficult.”

Twenty-six people — half men and half women, with an average age of 28 — spent two 12-day periods in the University of Surrey’s sleep lab. In one session they were allowed to sleep no more than six hours a night for seven nights. (They averaged a little more than 51 / 2 hours.) In the other session, their “sleep opportunity” was 10 hours, and they averaged 81 / 2.

During those parts of each session, the subjects — who were paid $4,500 for their 24 days in the research project — were able to watch television and movies, socialize and look out the window (but not go outside). When the week was over, however, they entered a different state: No entertainment, no stimulation, no daylight clues — and no sleep.

For 40 hours they lay semi-recumbent in bed in a room with low light and no windows. They interacted only with staff members, who gently shook them awake if they nodded off. Every hour they got a small amount of liquid nutrition, but no meals. Every three hours, blood was drawn.

The idea was to strip away as much activity as possible — except the activity of being awake.

The tests done during the 40 waking hours that followed a week of nights with up to 10 hours of sleep measured the effects of acute sleep loss. The tests done after a week of six-hour nights measured the effects of acute sleep loss on top of chronic sleep deprivation.

Measuring gene activity

The researchers measured the number of genes that were turned on and producing an RNA message, or transcript. They also measured the amount of transcript. The transcripts are evidence of work underway in cells. They are translated into proteins — structural, messenger, carrier and enzymatic molecules — and are also important regulators of cellular life.

The genes examined were in white blood cells. The assumption is that they reflect gene activity in other organs, such as the liver and brain. Whether that’s the case is uncertain. But it’s unlikely that the “blood transcriptome” presents a bigger or more dramatic picture of what’s happening elsewhere in the body.

Dijk, Colin P. Smith, Carla Moller-Levet and their colleagues found that the six-hour nights changed the level of transcripts of 711 genes; it was reduced in about 450 and increased in about 250.

The effects of those changes are hard to predict. A few are obvious, such as the increase of certain inflammation-causing cytokines in the bloodstream. But for many, the consequences of the changes in gene expression will require lots of study to figure out.

Chronic sleep deprivation also affected 1,855 circadian genes (which are about 9 percent of all genes). In circadian genes, the number of RNA transcripts rises and falls on a predictable 24-hour cycle: They oscillate. After a week of insufficient sleep, however, only 1,481 were still oscillating. In many of them, both the number of transcripts and the time of peak activity was different.

The researchers also identified genes whose activity depended on how long a person stayed awake. After a week of good sleep and then 40 hours of no sleep, there were 122 such genes. After a week of bad sleep, that number was up to 856.

In other words, not enough sleep day after day throws a lot of things off.

As with many important experiments, the one in Surrey raises as many questions as it answers: What effect does a nap have? Does a weekend of normal sleep reset the system? Do the gene-expression profiles get worse with longer periods of chronic sleep loss? Does what Dinges calls the “yo-yo lifestyle” of sleep restriction and recovery cause lasting physiological damage?

Sleep researchers will be trying to answer those questions now.

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