Go to Sleep! Why Messing With Your Body Clock May Make You Sick

We're hardwired to sleep at night and work during the day. A new study shows how disrupting that pattern can have serious impact on your health

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Few people really want to work at night. It’s dark, it’s lonely and it sets you apart from pretty much everyone else in the world — folks following the sensible schedule of rising in the morning, working during the day and sleeping at night. Oh, and then there’s the problem that a nocturnal schedule places you at greater risk of heart disease, diabetes, gastrointestinal illnesses and reproductive problems and, for people whose body clocks are misaligned for many years, higher rates of some cancers.

That’s the bad news. The worse news is that nobody knows really why disrupting the dark-light, sleep-wake cycle should have such an impact on health. Though researchers are unpacking the problem bit by bit, there’s still a lot of hand waving about circadian rhythms and body clocks and who knows what. Now, however, a new paper in the journal Science offers some explanation for one biological system that might be involved — and perhaps a bit of a warning for those working the night shift.

The author of the paper — Lora Hooper, a professor of immunology at University of Texas Southwestern Medical Center — does not typically study circadian rhythms. Rather, her work focuses on how gut bacteria interact with the immune system. In the course of working with mice engineered to lack a protein known as  NFIL3, which regulates immune cells, however, her group realized that all was not well with some of the animals. Specifically, the walls of their guts would come loose and start to poke out of their rears, a condition called rectal prolapse. That’s something even a mouse would just as soon avoid.

(MORE: Colon Cancer’s Newest Culprit: Gut Bacteria)

Looking into what was causing the condition, Hooper’s team discovered that the mice also had much higher rates of T helper 17 cells in their guts than healthy mice, which was not an anticipated result of eliminating NFIL3. Xiaofei Yu, a graduate student in Hooper’s lab, proceeded to examine what was going on in a series of experiments spread out over several years.

Yu and his colleagues knew that in normal mice, NFIL3 is under the control of a protein that is regulated by the circadian clock: certain sleep-wake cycles result in the body producing a lot of the protein, others result in less. That, in turn, would determine NFIL3 levels. In this case, the absent NFIL3 was the result of genetic tinkering, but the unhappy result — the inflammatory gut troubles leading to rectal prolapse — might be the same if circadian misalignment was to blame. The only way to know that for sure would be to mess with the sleep-wake cycles in healthy mice and see what happened.

The researchers began by first turning the lights on in their mouse cages six hours earlier than usual. They maintained that cycle for four days, then they turned the lights on six hours earlier still and gave the mice four days to adjust. They then repeated that clock-jumping process twice more. The result: the mice exposed to this artificial jet lag indeed had more T helper 17 cells in their guts. It would be sensible to conclude that they also had lower levels of NFIL3 — and they may have. The researchers did check for that, but, says Hooper, “The results were uninterpretable for technical reasons.” That’s an admitted shortcoming in the study, but one additional and very telling result at least partly compensates for that: the mice were also more apt to develop colitis, or an inflamed colon, when exposed to an irritant than normal mice, which sounds like the kind of problem that can result from circadian-related immune disruption.

(MORE: Less Sleep Linked to Alzheimer’s Disease)

So what was going on? Hooper, Yu and their colleagues suggest that in the course of its perambulations around the cell, NFIL3 binds to a bit of DNA that, when not bound, encourages the production of T helper 17 cells. But when NFIL3 and that promoter are entwined, the T cell production slows down. That on-and-off cycle may exist to allow only as many T cells as are needed to be manufactured and shuts things down after that. NFIL3 is around mainly in the nighttime, when mice, which are nocturnal critters, get up and go about their mousy business. Thus, the normal system is that during the day, when mice sleep, the circadian clock protein is at a high level and the T cells can develop. During the night, when the mice are active, the clock protein level goes down and fewer T cells are made.

“What’s the evolutionary rationale for this?” Hooper asks. “Candidly, I don’t have a solid scientific answer for that. But my speculation is that having T helper 17 cell development controlled by the circadian clock is a great way to control how many cells you actually produce, because they’re all being produced at the same time of day. It’s much easier to count everybody if they’re in the room at the same time than if they’re coming and going willy-nilly throughout the day and night.”

(MORE: Four Apps to Help You Sleep Better)

The greater meaning of these preliminary observations awaits further tests, especially tests in breeds of mice that are known to mimic the development of inflammatory disorders in humans, says Daniel Littman, a professor of immunology at NYU who was not involved in the research. For example, it would be helpful to see whether mice that are predisposed to get the mouse versions of inflammatory gut disorders get them at higher rates if their sleep-wake cycles are scrambled, which would suggest a link between what we’re seeing in mice and what we see in people. “Ideally, what you want to do is to shift the circadian clock in animals that can get spontaneous autoimmune disease,” Littman says. “That’s where this kind of work is leading.”

None of this will make life easier for the folks who have to punch into work at midnight and punch out when the rest of the world is getting up. But if it eventually leads to new treatments or therapies for body-clock-related illnesses, it could at least make the night owls healthier.

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