Poor sleep is known to affect human health in all kinds of harmful ways, with studies linking it to
everything from obesity and loneliness, to cardiovascular disease and early death. Scientists at Har
vard University have been exploring these connections in animal models and found a type of molecule
that appears to play a facilitating role in premature death, raising the prospect of new treatments
and furthering our understanding of the mysteries of sleep.
To investigate how sleep deprivation can be a driver of early death the Harvard scientists turned to
the trusty fruit fly, often used as a model in medical research due to the many genes that it share
s with humans, including those that regulate sleep.
The scientists set up an experiment where fruit flies were placed in individual tubes, with some gen
etically manipulated to express proteins that suppress sleep at warmer temperatures. After 10 days o
f this heat-induced sleep deprivation, mortality began to take off and by around day 20, all of the
fruit flies were dead. The control group that benefitted from normal sleep lived for around 40 days
in the tubes.
Searching for differences in cell damage, the scientists mostly came up empty-handed, with much of t
he tissues indistinguishable between the sleep-deprived and healthy flies. In the gut, however, the
team noticed a strong buildup of molecules known as reactive oxygen species (ROS) in the sleep-depri
ved group. In enough abundance these molecules can cause cell death by damaging DNA and other import
ant cellular components, and the team found that their numbers peaked after around 10 days of sleep
deprivation, as mortality began to increase.
“We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at m
arkers of cell damage and death, the one tissue that really stood out was the gut,” says study co-fi
rst author Alexandra Vaccaro. “I remember when we did the first experiment, you could immediately te
ll under the microscope that there was a striking difference. That almost never happens in lab resea
rch.”
Interestingly, the team found that when the deprivation was ended and the flies experienced regular
sleeping patterns, the ROS levels began to decline.
To further probe how the molecules might play a causal role in early death, the team treated the fli
es with antioxidant compounds that neutralize and clear out ROS from the gut, and also genetically m
anipulated flies to overproduce antioxidant enzymes in the gut for the same effect. These groups of
flies had normal or near-normal lifespans, despite being subjected to sleep deprivation.
“Even more surprising, we found that premature death could be prevented,” says senior study author D
ragana Rogulja. “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 flie
s.”
The team was able to draw similar conclusions in experiments on mice. Using a form of mechanical sti
mulation to keep the rodents awake for five days, the scientists observed elevated ROS levels in the
intestines compared to a control group.
While the team concludes that the buildup of ROS in the gut plays a “central role” in this form of p
remature death, it notes there is still plenty to learn about how it functions and what drives its a
ccumulation. With further work, the researchers hope this discovery can lead to treatments that coun
ter the effects of sleep deprivation in humans.
“We still don’t know why sleep loss causes ROS accumulation in the gut, and why this is lethal,” say
s Kaplan Dor. “Sleep deprivation could directly affect the gut, but the trigger may also originate i
n the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have s
ystemic effects, or some combination of these.”