Why is Sleep Deprivation so Bad for You? The Answer May Lie in Your Gut

Featured image credit: Anna Olivella

The Context: Chronic sleeplessness is associated with many disorders including heart disease, type 2 diabetes, cancer, obesity, and depression. Previous studies have also shown that prolonged lack of sleep can lead to death in animals, but it is not known exactly why.

The Study: It is a buildup of toxic oxygen-carrying molecules called ‘reactive oxygen species’ (ROS) in the gut that appears to lead to premature death in cases of extended sleeplessness in fruit flies, finds a new study in Cell by NYSCF – Robertson Neuroscience Dragana Rogulja, PhD, of Harvard University. The team also identified several compounds that could neutralize ROS and bring the flies’ lifespans back to normal.

The Importance: This study identifies an important link between chronic sleeplessness and premature death in flies that may also exist in humans, and points to the gut as a potential target for future therapies.

We all know how important a good night’s sleep is for healthy function, but prolonged sleep deprivation can lead to far worse consequences than fatigue and irritability — in some cases observed in animals and reported anecdotally in humans, it’s fatal.

What is it about lack of sleep that can cause death? According to a new study in Cell by NYSCF – Robertson Neuroscience Dragana Rogulja, PhD, of Harvard University, the answer could lie in the gut.

“We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation. We were surprised to find it was the gut that plays a key role in causing death,” said Dr. Rogulja, an Assistant Professor of Neurobiology in an article from Harvard Medical School. “Even more surprising, we found that premature death could be prevented.”

Restless Fruit Flies and the Gut

Sleep is necessary for almost every animal, especially humans, for whom chronic sleeplessness is associated with heart disease, type 2 diabetes, cancer, obesity, depression, and other disorders.

Fruit flies share many sleep-regulating genes with humans, and Dr. Rogulja’s lab decided to take a closer look at the cellular characteristics underlying sleep deprivation in these creatures.

The team first sought to keep the flies alive through physical shaking of the insects’ living chambers, but the flies were able to sleep through it. They then decided to genetically manipulate a certain protein in the flies’ brain cells that is sensitive to heat and would keep the flies awake when housed at 84°F.

The genetically altered flies, as well as a control group, were deprived of sleep for 10 days. By 20 days, all of the sleep deprived flies died, and the non-sleep deprived flies went on to live twice as long.

“We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut,” said Alexandra Vaccaro, PhD, a postdoc in Dr. Rogulja’s lab. “I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research.” 

The scientists found that the flies’ guts had a buildup of ROS (reactive oxygen species — oxygen-containing molecules that can harm cells when present in large quantities). ROS reached its peak accumulation at 10 days, when sleep deprivation was at its height.

The team then wondered, ‘what if we remove the ROS?’ They identified 11 anti-oxidative compounds (such as melatonin, lipoic acid, and NAD) that could neutralize ROS and administered them to sleep-deprived flies. The effectiveness of these compounds was striking: the flies went on to live to normal lifespans.

“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,” remarked Dr. Rogulja.

Next Steps

Dr. Rogulja’s team plans to continue studying the link between sleep deprivation and the gut.

“We still don’t know why sleep loss causes ROS accumulation in the gut, and why this is lethal,” said Yosef Kaplan Dor, PhD, another postdoc in Dr. Rogulja’s lab. “Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these.”

The scientists hope that better understanding this link could lead to therapies that prevent it, and in turn, better outcomes for people everywhere who experience sleep loss. 

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

“We need to understand the biology of how sleep deprivation damages the body, so that we can find ways to prevent this harm.”

Journal article:

Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut
Alexandra Vaccaro, Yosef Kaplan Dor, Keishi Nambara, Elizabeth A. Pollina, Cindy Lin, Michael E. Greenberg, Dragana Rogulja. Cell. 2020. DOI: https://doi.org/10.1016/j.cell.2020.04.049