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Sleep Deprivation Death Linked Causally to the Gut

Reporter : Irina Robu, PhD

Neuroscientists at Harvard Medical School identified an unexpected link between sleep deprivation and premature death. Their findings show that the possibility that animals might be able to survive without sleep, under certain circumstances. Their study with sleep-deprived fruit flies found that death was continuously by the accumulation of reactive oxidative species in the gut. And when the flies were given antioxidant compounds that neutralized and cleared ROS from the gut, the sleep-deprived animals remained active and had normal lifespans. Extra experiments in mice confirmed that ROS accumulated in the gut when they didn’t get enough sleep.

Yet, in spite of decades of study, researchers still haven’t revealed 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. However, studies have yet to yield conclusive results. In addition to impairing cognition, sleep loss leads to dysfunction of the gastrointestinal, immune, metabolic, and circulatory systems.

The Harvard Medical School team carried out a sequence 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. To screen sleep, the investigators used infrared beams to constantly track the movement of flies housed in individual tubes. Scientist show that flies can sleep through physical shaking, so they genetically manipulated fruit flies to express a heat-sensitive protein in specific neurons, the activity of which are known to suppress sleep. When flies were housed at 29°C the protein induced neurons to remain constantly active, thus preventing the flies from sleeping.

The scientists discovered that fruit fly mortality spiked after 10 days of temperature-induced sleep deprivation and all of the flies died by around day 20 and control flies that had normal sleep lived up to approximately 40 days in the same environmental conditions. Since mortality increased around day 10, the scientists looked for markers of cell damage on that and the preceding days. They noticed that the guts of sleep-deprived flies had a dramatic build-up of ROS. The buildup of ROS in the fruit fly guts peaked around day 10 of sleep deprivation, and when deprivation was stopped, ROS levels decreased.

To find out if ROS in the gut plays a causal role in sleep deprivation-induced death, the researchers next looked at whether preventing ROS accumulation could prolong survival. They tested dozens of compounds with antioxidant properties known to neutralize ROS and identified 11 that, when given as a food supplement, allowed sleep-deprived flies to have a normal or near-normal lifespan. These compounds, such as melatonin, lipoic acid, and NAD, were particularly effective at clearing ROS from the gut. Notably, the supplements did not extend the lifespan of non-sleep-deprived flies.

The role of ROS removal in preventing death was also confirmed by experiments in which flies were genetically manipulated to overproduce antioxidant enzymes in their guts. These flies had normal to near-normal lifespans when sleep deprived, but flies that overproduced antioxidant enzymes in their nervous systems weren’t protected from sleep-deprivation-related death. While the results demonstrated that ROS build up in the gut plays a central role in causing premature death from sleep deprivation, the researchers acknowledged that many questions are still without answers. At the same time, they found that insufficient sleep is identified to restrict with the body’s hunger signaling pathways, which lead to measure the fruit fly food intake to analyze whether there were potential associations between feeding and death. They found that some sleep-deprived flies ate more throughout the day compared with non-deprived controls.

The researchers are now working to identify the biological pathways that lead to ROS accumulation in the gut and subsequent physiological disruptions.

SOURCE

Death Due to Sleep Deprivation Linked Causally to the Gut, and is Preventable in Flies