The circadian cycles of sickness and health

Each year, many of us welcome small pleasures of autumn, like watching the leaves proceed through a spectrum of fiery jewel tones before raking them into big crunchy piles, bundling ourselves up in cosy sweaters as temperatures drop, and stealing an extra hour of sleep as millions of Americans turn their clocks back by an hour.

It’s hard to resist the appeal of ignoring the alarm clock and retreating into a mound of blankets on a dark and chilly morning, but the end of daylight savings time and its return in the spring are also accompanied by an array of unpleasant and sometimes life-threatening side effects. Studies routinely show higher incidences of car accidents, injuries, and even heart attacks on the days surrounding the biannual time change.

Distraction and irritability due to a sudden shift in sleep schedule can account for some of these effects, but our bodies are finely calibrated to the natural cycles of light and dark, and forcing them into a different rhythm can wreak havoc on our physical and mental health.

The biological function of sleep itself has routinely mystified neuroscientists, but we can universally agree that we feel pretty awful without it. Sleep disturbances are linked to mood disorders, and when we come down with a virus or an infection, it’s common to feel fatigued and to sleep excessively.

The relationship between the immune system and the internal clock stretches back billions of years and is thought by some researchers to be an ingenious strategy employed by ancient single-celled life forms to protect their delicate DNA by timing the production of protective enzymes during daylight hours, when they would be most susceptible to damage during cell division. Enzymes that are known to protect against DNA damage have been found to run on predictable 24-hour rhythms in most of the living things on earth.

These rhythms are locked to the natural cycle of night and day, but as humans have evolved and developed busy schedules and technological innovations that defy these cycles, scientists have begun to realize that our ability to burn the midnight oil may come at a cost to our physical health.

The darker winter months are periods of low moods for many people. While a variety of social factors can contribute to seasonal depression, carefully timed exposure to high-intensity illumination has proven to be a remarkably effective and relatively simple intervention.

Lining the very backs of our eyes are beds of light-sensitive cells, packed together in a structure called the retina. When we see the sun rise — or sit in front of a SAD lamp for a few minutes — these cells fire off messages to a small region of the brain called the suprachiasmatic nucleus.

Often referred to as the body’s “central pacemaker,” these bundles of neurons are a circadian relay station from the outside world to the rest of the body, firing in sync with the sun. A staggering number of genes are subject to circadian regulation. Those that coordinate our sleeping patterns are the first ones that might come to mind, but other processes we might not necessarily think would vary depending on the time of day are also controlled by circadian genes — things like blood pressure, the levels of circulating hormones in our bloodstream, and cells that rally to the cite of an injury or infection to fight off illness.

Extreme examples of some of the metabolic consequences of disrupting the natural light/dark continuum come from occupations that require employees to work overnight, reversing their normal sleep patterns. Long-term shift work is consistently associated with metabolic syndrome, whose symptoms include cholesterol and blood pressure elevation and may predict the development of diabetes.

Similar changes in metabolic factors are seen in mouse models of “social jet lag,” another artefact of the typical modern workweek that encourages people to sleep in and stay up later on weekends. The molecular reasons for this phenomenon are still unclear, but out-of-sync sleep seems to encourage cravings for high-calorie junk foods, like carbohydrates and fat. Changes in appetite and diet correspond to changes in the availability of glucose, one of the body’s major energy sources, throughout the day and into the night. The enzymes that process glucose are also subject to regulation by molecular pacemakers, subsiding when you would ordinarily be sleeping, and ramping back up during the active daylight foraging hours.

One possible explanation for these metabolic changes, then, is that eating inconsistently or at odd hours overwhelms the ability of these carefully timed energy production processes to effectively break down unexpected glucose deliveries.

Beyond broader metabolic disorders that can develop over long periods of living at odds with the sunlight, many studies have also uncovered detrimental effects on immunity that can occur on even shorter time scales.

Over the past decade, a series of studies done by Dr. Randy Nelson, currently a professor of neuroscience at the West Virginia University, has untangled the relationships between exposure to light and a variety of different health outcomes. One early study exposed hamsters to dim light throughout the sleep phase and then measured behaviour and brain structure two months later. Hamsters that had slept with the lights on not only exhibited depressed and anxious behaviour, but the structure of the neurons in the hippocampus, a region of the brain most commonly associated with the ability to learn and form memories, was also altered by nighttime light exposure.

More recent work by Dr. Nelson’s team has shown that these effects reach beyond the brain, to the immune system. Hamsters similarly exposed to dim light at night were also less resilient in the face of an immune challenge. Swelling, an indicator of a healthy inflammatory response, was dampened in these animals, and they were also generally more sluggish during the day. Most recently, the lab showed that dampened immune responses might even persist through the generations. In the offspring of hamsters exposed to light at night, the lab observed marked alterations in the levels of pro- and anti-inflammatory proteins in response to infection.

Male offspring in particular also experienced shorter, milder fevers compared to controls — another experimental indicator of a dampened immune response.

Most hamsters don’t face the kinds of complicated social pressures that people do: they aren’t compelled to wake up before sunrise, put on uncomfortable business casual attire, and spend their days in cubicles only to be compelled at the end of an exhausting week to join their co-workers for happy hour when they’d rather be on the couch with a cup of tea. It’s therefore tricky to generalize these findings to human models of disease when so many other factors are at play.

But as the Covid-19 pandemic has stretched endlessly through the seasons, many of us have found ourselves confined to our own personal hamster cages, bathed at all hours in the watery artificial daylight of our screens now that our social lives have been relegated to the virtual realm.

These unnatural new daily rhythms will undoubtedly take a toll on our mental and physical well-being, and the entanglement of circadian biology and immunity will be important public health considerations. Many studies have shown that the inflammatory and antibody-producing proteins that home to the sites of injury or attack invading pathogens also operate on a clock, with levels of many immune factors peaking during the day and dropping at night.

These findings support the idea that treatments might be more effective at certain times of day, and indeed, one study found that in a group of elderly patients who were vaccinated against a specific strain of the H1N1 influenza virus early in the morning, antibody concentrations persisted at higher levels in their bloodstreams for a longer period of time than in a separate group that received the vaccine later in the day.

As larger swaths of humanity have acquired access to wealth and technology, the pace of living for many people has fallen out of step with the elements. From artificial lighting to 24-hour high-speed transportation, human beings have engineered countless opportunities to stay active despite our evolutionarily ingrained imperative to rest as soon as the sun goes down.

New research offers greater insight into how our bodies rebel when we oppose our natural circadian urges. Rather than fuelling the search for increasingly clever pharmaceutical strategies to resist the pull of the sun, though, hopefully this work will compel us to reflect on ways to strike a gentler balance between our ambitious brains and our surroundings.