Death Due To Sleep Deprivation Linked Causally To The Gut, And Is Preventable in Flies

What isn’t clear is whether these effects on other systems are secondary consequences of changes to nervous system function, or whether they are independent and direct effects of sleep deprivation.

Harvard Medical School (HMS) neuroscientists have identified an unexpected, causal link between sleep deprivation and premature death.

Their study in sleep-deprived fruit flies found that death was always preceded by the accumulation of reactive oxidative species (ROS) in the gut.

When fruit flies were given antioxidant compounds that neutralized and cleared ROS from the gut, the sleep-deprived animals remained active and had normal lifespans. Additional experiments in mice confirmed that ROS accumulated in the gut when they didn’t get enough sleep.

The findings, reported in Cell, hint at the possibility that animals might be able to survive without sleep, under certain circumstances. The research could also point to new avenues of study that will help us understand the full consequences of insufficient sleep, and potentially the development of new approaches to counteracting the adverse effects of lack of sleep in humans.

“We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation,” said senior study author Dragana Rogulja, PhD, assistant professor of neurobiology in the Blavatnik Institute at HMS.

“We were surprised to find it was the gut that plays a key role in causing death. Even more surprising, we found that premature death could be prevented. 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 colleagues reported their findings in a paper titled, “Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut.”

Most of us will be familiar with the tell-tale signs that we’ve not had enough sleep. These may include tiredness and general fatigue, difficulty concentrating, and irritability.
The effects of more prolonged sleep deprivation can be more serious, and lead to disorientation, paranoia, and hallucinations.

“Countless clinical and experimental studies link insufficient sleep with serious health problems,” the authors wrote.

In humans, chronic insufficient sleep is associated with heart disease, type 2 diabetes, cancer, obesity, depression, and many other conditions. And while the link between total sleep deprivation and death has been reported in humans only anecdotally, “… sleep restriction can lead to premature death in model organisms, including dogs, rats, cockroaches, and flies,” the authors continued.

However, despite decades of study, scientists still haven’t discovered why animals die when they don’t sleep. In attempts to answer how sleep deprivation culminates in death, most research has focused on the brain, where sleep originates.

“Sleep is generated by neurons, so it has generally been assumed that death observed with sleep deprivation results from impaired brain function,” the team noted.

“This idea is supported by the significant cognitive decline noticeable after sleep loss.”

However, studies have yet to yield conclusive results. And, interestingly, the researchers added, “in addition to impairing cognition, sleep loss leads to dysfunction of the gastrointestinal, immune, metabolic, and circulatory systems.”

What isn’t clear is whether these effects on other systems are secondary consequences of changes to nervous system function, or whether they are independent and direct effects of sleep deprivation.

It’s also not known if any of these effects contribute to death in sleep-deprived animals.
Spearheaded by study co-first authors Alexandra Vaccaro, PhD, and Yosef Kaplan Dor, PhD, who are research fellows in neurobiology at HMS, the HMS team carried out a series of experiments in fruit flies, to search throughout the body for signs of damage caused by sleep deprivation.

Fruit flies share many sleep-regulating genes with humans. “In our search for factors that directly link sleep loss and death, we took an agnostic approach in terms of anatomy, examining multiple tissues in parallel,” the investigators wrote.

“Our first model was the fly because flies and mammals share core attributes of sleep and flies require sleep for a normal lifespan.”

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