The surprise reason sleep-deprivation kills lies in the gut
New research establishes an unexpected connection.
- 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.)
Image source: Tomasz Klejdysz/Shutterstock/Big Think
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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The idea of 'absolute time' is an illusion. Physics and subjective experience reveal why.
- Since Einstein posited his theory of general relativity, we've understood that gravity has the power to warp space and time.
- This "time dilation" effect occurs even at small levels.
- Outside of physics, we experience distortions in how we perceive time — sometimes to a startling extent.
Physics without time<p>In his book "The Order of Time," Italian theoretical physicist Carlo Rovelli suggests that our perception of time — our sense that time is forever flowing forward — could be a highly subjective projection. After all, when you look at reality on the smallest scale (using equations of quantum gravity, at least), time vanishes.</p><p style="margin-left: 20px;">"If I observe the microscopic state of things," writes Rovelli, "then the difference between past and future vanishes … in the elementary grammar of things, there is no distinction between 'cause' and 'effect.'"</p><p>So, why do we perceive time as flowing <em>forward</em>? Rovelli notes that, although time disappears on extremely small scales, we still obviously perceive events occur sequentially in reality. In other words, we observe entropy: Order changing into disorder; an egg cracking and getting scrambled.</p><p>Rovelli says key aspects of time are described by the second law of thermodynamics, which states that heat always passes from hot to cold. This is a one-way street. For example, an ice cube melts into a hot cup of tea, never the reverse. Rovelli suggests a similar phenomenon might explain why we're only able to perceive the past and not the future.</p><p style="margin-left: 20px;">"Any time the future is definitely distinguishable from the past, there is something like heat involved," Rovelli wrote for the <a href="https://www.ft.com/content/ce6ef7b8-429a-11e8-93cf-67ac3a6482fd" target="_blank"><em>Financial Times</em></a>. "Thermodynamics traces the direction of time to something called the 'low entropy of the past', a still mysterious phenomenon on which discussions rage."</p>
The strange subjectivity of time<p>Time moves differently atop a mountain than it does on a beach. But you don't need to travel any distance at all to experience strange distortions in your perception of time. In moments of life-or-death fear, for example, your brain would release large amounts of adrenaline, which would speed up your internal clock, causing you to perceive the outside world as moving slowly.<br></p><p>Another common distortion occurs when we focus our attention in particular ways.</p><p style="margin-left: 20px;">"If you're thinking about how time is <em>currently</em> passing by, the biggest factor influencing your time perception is attention," Aaron Sackett, associate professor of marketing at the University of St. Thomas, told <em><a href="https://gizmodo.com/why-does-time-slow-down-and-speed-up-1840133782" target="_blank">Gizmodo</a></em>.<em> "</em>The more attention you give to the passage of time, the slower it tends to go. As you become distracted from time's passing—perhaps by something interesting happening nearby, or a good daydreaming session—you're more likely to lose track of time, giving you the feeling that it's slipping by more quickly than before. "Time flies when you're having fun," they say, but really, it's more like "time flies when you're thinking about other things." That's why time will also often fly by when you're definitely <em>not</em> having fun—like when you're having a heated argument or are terrified about an upcoming presentation."</p><p>One of the most mysterious ways people experience time-perception distortions is through psychedelic drugs. In an interview with <a href="https://www.theguardian.com/books/2018/apr/14/carlo-rovelli-exploding-commonsense-notions-order-of-time-interview" target="_blank"><em>The Guardian</em></a>, Rovelli described a time he experimented with LSD.</p><p style="margin-left: 20px;">"It was an extraordinarily strong experience that touched me also intellectually," he said. "Among the strange phenomena was the sense of time stopping. Things were happening in my mind but the clock was not going ahead; the flow of time was not passing any more. It was a total subversion of the structure of reality."<br></p><p>It seems few scientists or philosophers believe time is completely an illusion.</p><p style="margin-left: 20px;">"What we call <em>time</em> is a rich, stratified concept; it has many layers," Rovelli told <em><a href="https://physicstoday.scitation.org/do/10.1063/PT.6.4.20190219a/full/" target="_blank">Physics Today</a>.</em> "Some of time's layers apply only at limited scales within limited domains. This does not make them illusions."</p>What <em>is</em> an illusion is the idea that time flows at an absolute rate. The river of time might be flowing forever forward, but it moves at different speeds, between people, and even within your own mind.
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