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.)
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."
Image source: Kinga Cichewicz/Unsplash/Hasbro/Big Think
- Most research in this area is done with non-human subjects, and this study validates earlier findings.
- The brain replays activities that occurred during wakefulness as you doze, or while it's "offline."
- Micro electrodes used in BCIs provide unprecedented access to brain functions.
People have probably always wondered what, exactly, is going on in our heads that produces our crazy-quilt dreams. Recent research suggests that it all has to do with memory consolidation as our brains weed through the prior day's experiences to identify the stuff that merits long-term storage.
There has been indirect evidence that part of the process involves mentally replaying the day's activities. A new study involving two subjects with implanted brain-computer interfaces (BCI) provides the most direct proof yet that this is indeed part of what's going on. "This is the first piece of direct evidence that in humans, we also see replay during rest following learning that might help to consolidate those memories," says first author of the study Beata Jarosiewicz
The study is the work of researchers from BrainGate, an academic research consortium involving scientists from Brown University, the Providence VA Medical Center, Massachusetts General Hospital, Case Western Reserve University, and Stanford University. "Replay of Learned Neural Firing Sequences during Rest in Human Motor Cortex" is published in the May 5 issue of Cell Reports.
Scientists' suspicion
Image source: National Cancer Institute/Unsplash
Our senses stay busy, pulling in new information all day. In addition to the events to which we pay attention, sights, sounds, smells, and so on are being received continually. From this barrage of stimuli we learn to recognize the things that require our attention, but even the things we barely notice consciously don't escape notice by our brains.
Those of us intrigued by our dreams find that most of what appears scrambled into them has made some sort of appearance in our waking lives over the last day or two. Sometimes it's those things directly, sometimes they're represented by some sort of symbolic stand-in — that movie star in your dream may be playing the part of someone actually in your life, for example — but the odd little bits that pop up make it clear that even the most casual inputs throughout the day stick, at least temporarily. But which stuff deserves remembering for a long time?
According to "Memory, Sleep and Dreaming: Experiencing Consolidation":
"There is strong evidence that at least one function of sleep is to 'consolidate' fragile new memory traces into more permanent forms of long-term storage, integrating key features of recent experience with existing remote and semantic memory networks."
The same article notes, "Behavioral studies in humans have clearly demonstrated that post-learning sleep is beneficial for human memory performance in a variety of learning domains."
Previous, non-human research
Hippocampus in red
Image source: Life Science Databases/Wikimedia
The earliest research suggesting that the brain replays recent experiences as we sleep — when our brains are ""offline," so to speak — showed that hippocampal "place cells" of rodents re-fired in sleep in the same order as they had when the animals ran along a track just prior to sleeping. (The hippocampus is a brain region associated with memory.)
Since then, activity replays while offline have been observed in various cortical and subcortical areas in non-humans. Non-invasive evidence from humans has also provided further, albeit indirect, evidence, suggesting replays of cerebral activity during sleep for:
- odors to which the subjects had been previously exposed
- leaning-related brain activity
- motor areas following movement learning.
The new study
Image source: Cash, et al
Lacking has been direct evidence of such replays in humans. Jarosiewicz points out, "There aren't a lot of scenarios in which a person would have a multi-electrode array placed in their brain, where the electrodes are tiny enough to be able to detect the firing activity of individual neurons." Electrodes approved for human implantation, such as those used in treating Parkinson's or epilepsy, aren't sensitive enough.
The solution was the brain-computer interfaces (BCIs) developed by BrainGate. These are intracortical micro electrode arrays that allow patients with severe motor disabilities to regain a measure of control by moving mouse cursors and operate robotic arms and assistive devices with their mind, or more specifically, brain waves. (We've written before about the powerful potential of BCIs before at Big Think.) BCIs had already been implanted in the study's two participants as part of clinical trials for the device.
For the study, they took naps both before and after playing a version of the popular game Simon as brain activity was monitored through their BCIs. The researchers observed the same neuronal patterns firing off as the game was played and then again during the post-play nap.
The authors report, "We compare the firing rate patterns that caused the cursor movements when performing each sequence to firing rate patterns throughout both rest periods. Correlations with repeated sequences increase more from pre- to post- task rest than do correlations with control sequences, providing direct evidence of learning-related replay in the human brain."
Jarosiewicz enthuses, "All the replay-related memory consolidation mechanisms that we've studied in animals for all these decades might actually generalize to humans as well."
While the exact mechanisms the brain uses to sort and consolidate memories during sleep remain unknown, this study nonetheless supports the notion that answers derived from animal studies may turn out to be applicable to human beings as well, something that can't be assumed. It's an impressive testament to the use of human microscale neural recording systems in research.
For now, Jarosiewicz says we can probably take for granted conventional wisdom that getting a good night's sleep "before a test and before important interviews" can genuinely help. At the very least, now "we have good scientific evidence that sleep is very important in these processes."
