Sleep better: New study reveals what happens to a body when you don’t

Nearly all animals, including humans, sleep or exhibit sleep-like behavior. But despite its universality, sleep remains one of science's greatest mysteries.

We know sleep serves cognitive, cardiovascular, metabolic, and immune purposes, but scientists haven't yet pinned down why it's actually essential to survival. But in a new study, in fruit flies and mice, scientists claim to have answered the age-old question: Why do we need sleep to live?

By depriving animals of sleep and comprehensively analyzing the bodily effects, the team uncovered a causal link between sleep deprivation and premature death. After days of complete lack of sleep, molecules known as reactive oxidative species (ROS) accumulated in the animals' gut, preceding death.

However, when given antioxidant compounds that neutralized and cleared ROS from the gut, sleep-deprived flies remained active and had normal lifespans. This discovery hints at the potential to develop future therapies that can offset the negative health effects of sleeplessness in humans, the researchers say.

"We were surprised to find it was the gut that plays a key role in causing death," senior study author Dragana Rogulja, a neurobiology researcher at Harvard Medical School, tells Inverse. Many scientists assume sleep deprivations' lethality stems from impaired brain function.

"Even more surprising, we found that premature death could be prevented," Rogulja says. "Each morning, we would all gather around to look at the flies — with disbelief, to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies."

Rogulja and her team published the study Thursday in the journal Cell.

Staying awake — One major barrier to advancing sleep science is that it's challenging and often, unethical, deprive humans of sleep for prolonged periods and study the health effects, Rogulja explains.

When humans don't get enough sleep, common symptoms can set in: tiredness, fatigue, difficulty concentrating; irritability. When sleep deprivation is prolonged, people can experience disorientation, paranoia, and hallucinations.

Ultimately, without sleep, animals die — as seen in this study.

"The closest evidence to say that sleep is really essential for life is the fact that not only that you see it all over the animal kingdom, but experimentally when animals are sleep deprived, they die," Rogulja says. "As far as we can tell, there's nobody that can live without sleep."

To find out why, the team experimented with fruit flies, which share many sleep-regulating genes with humans.

The team monitored the flies' sleep with infrared beams, which constantly track the movement of flies housed in individual tubes.

"Every time we could neutralize ROS in the gut, we could rescue the flies."

To keep them from dozing off, they genetically manipulated the fruit flies to express a heat-sensitive protein in specific neurons, known to suppress sleep. When flies were housed at 84 degrees Fahrenheit, the protein-induced neurons remained constantly active. In turn, the flies stayed totally awake for days on end.

After 10 days of sleep deprivation, mortality spiked among the fruit flies. All died by day 20. Flies in a control condition who slept normally lived 40 days.

Researchers analyzed the tissue of different parts of the fruit flies and discovered that no parts of the body showed remarkable change or unusual damage, other than the gut.

The guts of sleep-deprived flies had a dramatic buildup of ROS, the highly reactive, oxygen-containing molecules. In large amounts, ROS can damage DNA and other components within cells, leading to cell death.

The accumulation of ROS peaked around day 10 of sleep deprivation, and when deprivation was stopped, ROS levels decreased. Death was always preceded by the accumulation of ROS in the gut.

Then, the team tested dozens of compounds with antioxidant properties known to neutralize ROS to see if they might be able to prevent ROS build up. They identified 11 that, when given as a food supplement, allowed sleep-deprived flies to have a normal or near-normal lifespan. These antioxidants didn't extend the animals' lives that got adequate sleep but seemed to buffer the health consequences for sleepless flies.

"Giving antioxidants through food — if it clears ROS — it rescues lifespan," Rojuljia says. "We were shocked when we saw this. It honestly like seemed pretty crazy and that's why we took several years to make sure that this is right."

"There's nobody that can live without sleep."

They also looked at what happened when they manipulated the fruit flies to genetically express antioxidant enzymes directly in the gut— and found the same positive, lifesaving effect.

If this phenomenon is conserved in humans, and Rojuljia expects it will be, there may be a way to efficiently neutralize ROS and get rid of some of the negative consequences of sleep loss.

The team also replicated the experiment in mice and found the same "striking" accumulation of ROS in their guts. The researchers used gentle, continuous mechanical stimulation to keep mice awake for up to five days. Compared to control animals, sleep-deprived mice had elevated ROS levels in the small and large intestines but not in other organs.

Taken together, the results demonstrate that ROS buildup in the gut plays a central role in causing premature death from sleep deprivation.

Still, scientists still don't know why sleep loss causes ROS buildup, or why it's lethal.

"This is the bad thing that happens when you don't sleep, but this may not be the daily function of sleep," Rojuljia explains. "It could be that this is a uniquely stressful condition."

Surviving sleeplessness — Chronic insufficient sleep is associated with heart disease, type 2 diabetes, and high blood pressure. One in three Americans doesn't get the recommended seven hours of sleep nightly.

Most sleep aide products aim to help people doze off, but none, Rogulja says, help buffer the effects of little sleep. Developing therapies to protect the health of those facing chronic sleep loss is desperately needed, especially for new parents or shift workers who regularly don't get enough, she adds.

"So many of us are chronically sleep-deprived. Even if we know staying up late every night is bad, we still do it," Rogulja says. "We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

Abstract: The view that sleep is essential for survival is supported by the ubiquity of this behavior, the apparent existence of sleep-like states in the earliest animals, and the fact that severe sleep loss can be lethal. The cause of this lethality is unknown. Here we show, using flies and mice, that sleep deprivation leads to accumulation of reactive oxygen species (ROS) and consequent oxidative stress, specifically in the gut. ROS are not just correlates of sleep deprivation but drivers of death; their neutralization prevents oxidative stress and allows flies to have a normal lifespan with little to no sleep. The rescue can be achieved with oral antioxidant compounds or with gut-targeted transgenic expression of antioxidant enzymes. We conclude that death upon severe sleep restriction can be caused by oxidative stress, that the gut is central in this process, and that survival without sleep is possible when ROS accumulation is prevented.