The surprise reason sleep-deprivation kills lies in the gut

New research establishes an unexpected connection.

Image source: Vaccaro et al, 2020/Harvard Medical School
  • A study provides further confirmation that a prolonged lack of sleep can result in early mortality.
  • Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
  • When the buildup is neutralized, a normal lifespan is restored.

We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?

A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.

The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.

An unexpected culprit

The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.

What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.

"Even more surprising," Rogulja recalls, "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." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)

fly with thought bubble that says "What? I'm awake!"

Image source: Tomasz Klejdysz/Shutterstock/Big Think

The experiments

The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.

You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.

For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.

Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.

The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.

However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "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." She adds, "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 experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.

As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.

The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "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 HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.

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

Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

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Dr. Kate Biberdorf explains why boiling water makes it safer and how water molecules are unusual and cool.

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Scientists figured out how a certain treatment for skin cancer gives some patients a visual "superpower."

Photo Credit: Joshua Rodriguez / Unsplash
  • In the early 2000s, it was reported that some cancer patients being treated with chlorin e6 were experiencing enhanced night vision.
  • Using a molecular simulation, researchers discovered that a chlorin e6 injection under infrared light activates vision by changing retinal in the same way that visible light does.
  • Researchers hope that this chemical reaction could one day be harnessed to help treat certain types of blindness and sensitivity to light.


In the early 2000s, it was reported that a certain kind of skin cancer treatment called photodynamic therapy, which uses light to destroy malignant cells, had a bizarre side effect: It was giving patients enhanced night time vision.

An essential component to this therapy is a photosensitive compound called chlorin e6. Some people being treated with chlorin e6 were upset to discover that they were seeing silhouettes and outlines in the dark. Researchers think they might finally know why this happens.

The chemistry of vision

Rods and cones photoreceptors in a human retina.

Photo Credit: Dr. Robert Fariss, National Eye Institute, NIH / Flickr

"Seeing" happens when a series of receptors in the retina, the cones and rods, collect light. Rods contain a lot of rhodopsin, a photosensitive protein that absorbs visible light thanks to an active compound found in it called retinal. When retinal is exposed to visible light, it splits from rhodopsin. This then allows the light signal to be converted into an electrical signal that the visual cortex of our brains interprets into sight. Of course, there is "less light" at night, which actually means that light radiation is not in a domain visible to humans. It's at higher wavelengths (the infrared level) that retinal is not sensitive to. Hence, why we can't see in the dark like many critters can.

But the vision process can be activated by another interaction of light and chemistry. As it turns out, a chlorin e6 injection under infrared light changes retinal in the same way that visible light does. This is the cause of the unforeseen night vision side effect of the treatment.

"This explains the increase in night-time visual acuity," chemist Antonio Monari, from the University of Lorraine in France, told CNRS. "However, we did not know precisely how rhodopsin and its active retinal group interacted with chlorin. It is this mechanism that we have now succeeded in elucidating via molecular simulation."

Molecular simulation

"Molecular simulation" is a method that uses an algorithm that integrates the laws of quantum and Newtonian physics to model the functioning of a biological system over time. The team used this method to mimic the biomechanical movements of individual atoms – that is, their attraction or repulsion to one another – along with the making or breaking of chemical bonds.

"For our simulation we placed a virtual rhodopsin protein inserted in its lipid membrane in contact with several chlorin e6 molecules and water, or several tens of thousands of atoms," Monari explained to CNRS. "Our super-calculators ran for several months and completed millions of calculations before they were able to simulate the entire biochemical reaction triggered by infrared radiation." In nature, this phenomena occurs within fractions of a nanosecond.

The molecular simulation showed that when the chlorin e6 molecule absorbs the infrared radiation, it interacts with the oxygen present in the eye tissue and transforms it into reactive, or singlet, oxygen. In addition to killing cancer cells, "singlet oxygen" can also react with retinal to enable a slightly enhanced eyesight at night, when light waves are at the infrared level.

Future potential

Now that researchers know why the "supernatural" side effect occurs, they may be able to limit the chance of it happening to patients undergoing photodynamic treatment. Thinking further out, the researchers hope for the possibility that this chemical reaction could be harnessed to help treat certain types of blindness and sensitivity to light.

Ultimately, researchers say that this has been a big flex for the power of molecular simulations, which can give us astonishing scientific insights like this.

"Molecular simulation is already being used to shed light on fundamental mechanisms – for example, why certain DNA lesions are better repaired than others – and enable the selection of potential therapeutic molecules by mimicking their interaction with a chosen target," Monari told CNRS.

Don't hold your breath on night vision eyedrops though.

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