On April 14, a 50-year-old Spanish woman emerged from her temporary dwelling place, 230 feet under the rolling hills of Andalusia. Up until that moment, Beatriz Flamini had been isolated in a cave for a 500-day challenge, without natural light, news or even sight of her own reflection.
Flamini is an extreme athlete known for climbing and mountaineering — forever on the lookout for “experiences very few human beings have had.” But for chronobiologists at the universities of Granada, Almería and Murcia, her expedition was an opportunity to monitor the human body unprompted by the usual signals that give structure to our days.
It can often feel like daily life’s alarm clocks, work schedules and appointments are a rigid imposition on an otherwise free-flowing natural world. Yet biology is suffused with similar clocks.
In the 4th century B.C. a ship’s captain under Alexander the Great reported seeing tamarind leaves which closed at night and started to open at sunrise, unfurling themselves toward midday. The 13th century “Noon and Midnight Manual” describes a principle of Chinese traditional medicine whereby qi — the body’s vital force — flows to different organs across twelve two-hour increments, repeating every 24 hours.
In 1729, French scientist Jean-Jacques d’Ortuous de Mairan studied the daily movements of Mimosa pudica leaves, observing that they continued even in complete darkness. Two hundred years later, the German ethologist Ingeborg Beling reported similar cycles in the animal kingdom. Her paper, “On the Time Memory of Bees,” describes the punctuality of swarm behaviors which can be trained to different times of day.
Today we know that the master timekeeper in the human body is in the suprachiasmatic nucleus, or SCN, a cluster of neurons in the hypothalamus that receives input from cells in the retina that are responsive to visible blue light from the sun. That light suppresses melatonin, the sleep hormone, and times the cascade of energizing chemistry that helps us wake up in the morning and kickstart our day.
There is more than one clock, however. Various systems in your body, including the cardiovascular, metabolic, immune and reproductive systems have their own “peripheral clocks,” which cycle through active and resting phases. In fact, the same is true for the trillions of cells and hitchhiking microbes that make us who we are.
The Circadian Revolution
Over the last few years, there has been a groundswell of podcasts, wellness apps and self-improvement social media videos alerting a mass audience to the potential of applying circadian science. It was a slightly non-PC meme in which an anxious party attendee plans to head home “to protect my circadian rhythm” that made me think new, younger audiences were taking note.
We’ve progressed from what was really fringe science in the 1980s “to a truly exquisite mechanistic understanding of how these rhythms are generated,” Russell Foster, professor of circadian neuroscience at the University of Oxford, tells me. Foster’s book “Life Time: The New Science of the Body Clock, and How It Can Revolutionize Your Sleep and Health,” has been a surprise best seller. “It’s very satisfying for me to see how it’s exploded,” he says.
For example, a viral YouTube video entitled “The Optimal Morning Routine – Andrew Huberman” by After Skool animates advice from the wildly popular Stanford professor, who recommends viewing outdoor light within an hour after waking, even if it’s cloudy. This is because light exposure is by far the most powerful way to “entrain” the cybernetic complex of clocks within our bodies.
To borrow an analogy from biochemist Urs Albrecht and colleagues’ “orchestra” model, the SCN is like a musical conductor: when the symphony is playing in unison, the harmonious uplift in focus, memorization, physical performance, immunity and restful sleep is profound.
“In five years of training most medical students won’t hear anything about circadian rhythms or sleep,” Foster tells me. Meanwhile, “if I came up with a drug that halved my chances of stroke, cancer, over a five-year period [just some of the potential benefits of a synchronized circadian system], I’d be off to Stockholm to pick up my Nobel Prize.”
The word circadian — meaning approximately (circa) a day (diem) — was coined by the Romanian-born scientist Franz Halberg, whose laboratory at the University of Minnesota proved that humans operate according to various cycles. There are not just day-long cycles, but also shorter, “ultradian,” and longer, “infradian” cycles.
Halberg showed that human circadian rhythms were endogenous — meaning internally produced — but could be kept in line by what the German biologist Jürgen Aschoff called zeitgeber, literally time-givers, or cues in the environment.
All life on Earth evolved with the influence of the planet’s rotation: around 21 hours when complex life emerged 600 million years ago, slowing gradually — due to gravitational friction from the moon — to 23 hours, 56 minutes and 4 seconds today. Every time we fly across the planet, party until dawn, or spend the morning scrolling with the blinds down, we misalign ourselves with what our various organs, hormones and neurophysical processes are preparing for.
Perils associated with desynchronization may include poor sleep, indigestion, depression and anxiety, lowered fertility, increased risk of injury, heart attack, stroke and heightened vulnerability to germs and viruses. A disrupted circadian rhythm impairs executive function in the brain (things like selective attention, working memory and self-control). It exaggerates glucose intolerance and increases the odds of metabolic syndrome, obesity and Type 2 diabetes, each of which in turn worsens health outcomes. Chronic disruption, as with shift work, may even produce epigenetic changes that may be passed between generations.
Nurses are one of the best-studied professional groups and may have greater risk of breast, endometrial and colorectal cancer. Many cancer-related genes oscillate, switching off and on, under circadian control. As Foster notes in “Life Time,” multiple studies have linked a disrupted circadian system to “an increased susceptibility to cancer development in all key organ systems in humans, including breast, ovarian, lung, pancreatic, prostate, colorectal and endometrial cancers, non-Hodgkin’s lymphoma (NHL), osteosarcoma, acute myeloid leukemia (AML), head and neck squamous cell carcinoma and hepatocellular carcinoma.”
There are drugs in development that can “drive” the clock in cancer cells, where circadian disruption has been shown to increase the pace of tumor growth. In cases of Parkinson’s, Alzheimer’s and dementia, the strong links between circadian sleep disorder suggest to Foster that the restoration of sleep-wake circadian rhythm will hopefully slow the diseases’ progression if not ward off their arrival to begin with.
“Because SCRD (Sleep and circadian rhythm disruption) can exacerbate the symptoms of dementia and PD (Parkinson’s disease), it is important to think of SCRD stabilization as a therapeutic target,” he writes.
From the start, chronobiologist Franz Halberg was interested in how heart surgery and cancer treatment received at different times of day might influence outcomes. In other words, he was considering the ways that time — or rather timing — might be thought of as an aspect of healing, a “fourth dimension”, as some refer to it, fundamental to medicine, wellness and peak performance.
Stop All The Clocks
“We’re all so interested in sleep now, but sleep is an output of the circadian clock, and it’s one thing,” says Mickey Beyer-Clausen, cofounder and CEO of Timeshifter, a technology platform that offers personalized behavioral plans to reduce the impact of jet lag and shift work.
“People with jetlag think ‘Oh, I just feel off for a couple of days.’ No. You’ve disrupted every single organ in your body. You’re going to get sick more easily because your immune function is weak, and you’re going to have an upset stomach because you’re eating a steak when it’s 2 a.m. in your biology.”
Timeshifter’s goal is to provide access to advice once reserved for performance athletes and astronauts in the form of apps and partnerships with organizations such as United Airlines and Axiom Space.
You can think about space like “the ultimate business trip,” Beyer-Clausen says. Astronauts “need to hit the ground running. They can’t wait four or five days to get over jet lag.”
Spacewalks, which last up to eight hours, involve seeing sunrise and sunset every 45 minutes, totally disorienting the body’s clocks. That’s why there’s an LED light system that mimics dawn, day and dusk on the ISS.
Timeshifter’s apps suggest windows during which users should sleep, view light, reduce it, ingest caffeine or melatonin, with additional “practicality filters” for unshakeable commitments. In the case of long-haul flights, you “shift” your circadian clock gradually in the days before departure. This is how top-tier athletes, for example, show up ready to compete.
Formula 1 support teams are known to join the drivers in shifting their rhythms days before the race to the time zone of the race. Mars rover crews live on Martian time throughout their missions, with days almost 40 minutes longer than Earth’s, slipping gradually out of kilter with the environment around them. Speaking to reporters after exiting the cave, Beatriz Flamini claimed timelessness was a wonderful experience. “I’m still grieving for the cave,” she told the BBC in a story in June.
Strange findings have emerged from interventions in the mechanics of the body clock. In fact, it’s long been observed that extended wakefulness can temporarily lift depression, and “darkness retreats” are trending, according to the magazine, Glamour. In the absence of external cues, internal synchrony is achieved, though most of us are not extreme mountaineers, and a body out of sync with the world around it is unlikely to thrive.
In 2019 the writer and photographer Matt Colquhoun took part in a trial of “triple chronotherapy,” an experimental treatment focused on individuals with drug-resistant bipolar disorder. According to the doctor who prescribed it, the treatment’s origins can be traced to the 19th century when a German schoolteacher reported she could temporarily cure depression by riding her bike all night. In 1976, Dr. Burkhard Pflug at the University of Tübingen published an experiment with patients undergoing sleep deprivation to alleviate depression. The treatment showed a “marked improvement” in the short term — but relapse was high.
Decades later, a protocol named “triple chronotherapy” was developed by staff at the San Raffaele Hospital in Milan, and included lithium, sleep deprivation and timed light exposure. When the regimen was trialed in London in 2019, there was no lithium involved. Instead, patients were required to stay awake all night — under supervision — before sleeping at 5pm the following day.
According to the timetable, in the four days that follow, bedtime is advanced by two hours each evening until it settles into an 11 p.m. to 7 a.m. rhythm. Every morning, at 7 a.m., patients must view bright light. They must wear amber glasses for two hours before bed. This is then followed up with morning bright-light therapy between 7 a.m. to 9 a.m. for six months.
It’s “like Ctrl-Alt-Delete and resets your internal clock,” writes David Veale, the doctor who led the trial in which Colquhoun took part, on his website.
Coloquin wrote in a blog post immediately after treatment: “I have not felt this good in two years and it has transformed every part of my life almost immediately.” When I checked in with them recently, they told me they had not repeated the protocol because “though it worked wonders for me and was very useful in the controlled environment of the trial, to play with my own sleeping patterns unsupervised is something I’ve been reluctant to do, in case it all goes wrong!”
The Great Healer
A 2016 randomized double-blind study found that viewing sunlight for 30 minutes each morning was a more effective treatment for major depression than Prozac alone during the same period. When combined, the treatment was most effective. Outdoor light can range in intensity from 1,000 lux on a cloudy winter day to 100,000 lux in the summer.
By comparison, indoor lights tend to max out in the hundreds. Even the most obscenely over-lit supermarket is unlikely to exceed 1,000 lux. All this means the amount of time we spend outdoors should increase, not decrease, as the days grow shorter in the autumn.
It’s not just our psychology that is best served by organizing our days, where possible, in alignment with the daily rhythms for which our bodies are primed. There’s increasing evidence that the time of day when we take medicines has a notable influence on their effect.
“We already know of at least two drugs whose administration should be timed,” says Elizabeth Klerman, a professor of neurology at Harvard Medical School who uses mathematical analysis to understand the interplay between time of day, sleep-wake cycles and biological clocks. “Statins should be given at night and steroids should be given in the morning.”
Cholesterol normally increases at night, between midnight and 6 a.m., so short-acting statins (in the four- to six-hour range) should be taken before bed to align with the night-time production of cholesterol. Cortisol meanwhile rises between 38 and 75 percent within the first hour after waking. Taking Aspirin before bedtime reduces the chance of platelets clumping together to form unwanted blood clots and helps prevent heart attacks and stroke, which are more common in the morning as temperature and blood pressure rise to kick start the day.
After 27 years at Bringham and Women’s Hospital in Boston, Klerman began a new role at Massachusetts General Hospital where she works to apply sleep and circadian science across neurology, psychiatry, substance abuse, pediatrics and anesthesia.
When the hospital first began giving staff Covid vaccines in 2021, the hospital recorded the time of day and collected feedback on reported side effects. Two papers she co-authored found antibody production increased when vaccination took place in the afternoon while non-allergic side effects increased between 6 and 11 a.m.
“It’s way more important for people to get vaccinated than to worry about time-of-day effects,” she says, “but maybe these results will be encouraging for those who are worried about side effects or who need to care for a loved one the same day.”
This type of research has huge implications for drug development. Consider the use of rodents as test subjects. Pre-clinical studies use mice for their anatomical, physiological and genetic (99%) similarity to humans. But mice are nocturnal.
A 2020 study described the use of medicines that reduce nerve death in the event of a stroke. It found the treatment most effective when mice were in their sleep phase — which is when labs are open. The results failed to translate to humans until they were given at night.
“There may be drugs or interventions out there that didn’t work because they were studied at the wrong circadian time,” Klerman tells me. “If you’re a drug company and you can show there’s a time-of-day effect then you only have to test when there’s the biggest effect or smallest side effect.”
In 2017, three scientists, Jeffrey C. Hall, Michael Rosbash and Michael W. Young, won the Nobel Prize for their work uncovering the molecular mechanisms that power the circadian clock, a beautiful feedback loop that causes genes to switch on and off as proteins are produced and move around the cell.
Mutations in clock-controlled genes are known to cause enormous problems with appetite, sleep and hormonal regulation. Migraines are often reported at the same time of day and even at the same time of year. Any medicine or remedy must be designed to act when symptoms or risks are likely to be highest.
The skin is our largest organ — an essential weapon in our immune defense — and behaves differently in the daytime when it is braced against UV, bacteria, viruses and pollutants. During the night the skin becomes porous as it undergoes shedding and renewal, making us more vulnerable to invaders.
Another potentially enormous area for application is timed chemotherapy. Because nearly all cells in the human body are driven by 24-hour molecular clocks and control things like detoxification and DNA repair, treatments should be administered at times of day that allow non-cancerous host tissue cells the best chance at recovery. Multiple studies have found that the timing of chemotherapy treatment influences its necessitated dosage, the severity of side effects and the likelihood of relapse.
Yet with healthcare systems already under strain, the needs of doctors and nurses — for example, bright lights for their intricate work — won’t necessarily align with the circadian rhythms of the patients who rely on them. One way around this might be to alter patients’ internal clocks by using plans like those offered by Timeshifter. Another could be timed pumps that automate chemotherapy delivery.
Chronodesign
At present, most high schools in the U.S., Singapore and Germany commence before 8:30 a.m. despite evidence that later start times increase sleep duration, reduce daytime sleepiness, alleviate depression and improve exam results. Hospitals and nursing homes often require patients to stay indoors without regard for the many ways that timed light exposure and exercise can aid sleep and improve health, especially in patients with dementia.
Yet, despite the wealth of data in the scientific literature suggesting the importance of circadian cycles for human health, one issue, in particular, makes me skeptical of our ability for radical change in line with this new knowledge: daylight saving time.
“We circadian biologists are of a person unanimous that no we shouldn’t have it,” says Russell Foster. Daylight saving time (or DST) has been associated with daytime fatigue, mental health problems and less sleep. More heart attacks, strokes, workplace injuries and even fatal car crashes are reported in the week following the clock’s spring leap forward.
Even worse, we spend the next six months of the year out of whack with the position of the sun. The argument that this saves energy was disproven long ago, and despite unanimity within science, many countries trundle on without the means to fix this mistake.
Nations that have abolished DST include Iceland, Argentina, Brazil, Kazakhstan and Russia. The EU held a consultation in 2018 which saw the vast majority of its 4.6 million participants vote to end daylight saving time but has yet to implement the change.
Alarmingly, in the U.S., a bill called the “Sunshine Protection Act of 2023” has been proposed that would permanently enshrine daylight saving time rather than standard time, keeping citizens out of step with the sun year-round.
Meanwhile, China remains committed to using a single time zone despite its five geographical time zones spanning 3,100 miles east to west. This means much of the country’s social clock (used to coordinate daily life) corresponds to Beijing’s natural clock — where the sun is at its highest around noon. As a result, in Kashgar, the country’s westernmost city, the sun rises two-and-a-half hours later than it does in Beijing.
Till Roenneberg, a chronobiologist at Ludwig-Maximilian University (LMU) in Munich associated with the concept of “social jet lag,” has studied the single European time zone, which stretches from eastern Poland to western Spain. Until the German occupation of Luxembourg, Belgium and France during World War II, each nation ran on Greenwich Mean Time, a time zone with which they are more closely aligned.
The same is true for Nazi-allied Spain, much of which lies to the west of the UK. Roenneberg found that peoples’ chronotypes — colloquially referred to as the difference between morning larks and night owls — would shift across the countries that employ Central European Time in accordance with the time at which they see dawn light.
In Dan Beuttner’s Blue Zones project, which looks at the places on Earth where people live longest, Beuttner focuses primarily on the positive impact of diet, community and exercise. But it’s also true that people in places like Sardinia, Italy, and Japan’s Okinawa rise with the sun and go to bed not too long after it sets. “They have a very similar schedule every day,” says Timeshifter’s Clausen-Meyer. “There’s no doubt in my mind that diet, exercise and circadian stability are the three pillars of longevity and health.”
It is the morning’s specific wavelength of visible blue light upon which performance, digestion, sleep, mental clarity and longevity hangs (interestingly, the middle hours of the day are considered a circadian “dead zone” without the same power to shift the clock).
If those in authority grasp the power of circadian science to improve our lives, we might expect to see changes in how we design buildings to encourage or block light at different times of day, or labor laws that mandate health-oriented benefits and appropriate compensation for valuable shift workers.
“Tonight I’m on a call to Singapore at 11 p.m. for two hours,” says Clausen-Beyer. “But I know how to deal with it: I’ll wake up at the same time and view sunlight then take a nap later. The world has moved on. We need shift workers. We just need to be aware of the time, it is in our biology, and deal with our circumstances in the best way.”
Because viewing morning light is the most powerful way to entrain our circadian system, Clausen-Beyer ensures his internal clocks remain aligned, despite being temporarily sleep-deprived. A short nap can help and is better than slipping into a new time zone without having gone anywhere.
Over 270 years ago the Swedish botanist Carl Linneas proposed a “flower clock” in which different species would be arranged according to the time of day at which they opened, closed and released their unique scents. Though the plan remains unrealized, various horticulturists have tried to revive it over the years, lured by the dream of ecological synchrony.
This fall Apple Watch users will see the number of hours they spend in daylight incorporated into their health app. Meanwhile, trends suggest that people of all ages are shifting social activities to earlier in the day. As with Linneas’s imagined garden, principles of chronodesign, chronotherapy and chronoethics applied in hospitals, schools, homes and workplaces could offer a universal baseline, more in tune with our biology, to help us orient ourselves.
It’s safe to assume that life will find ways to knock us off schedule — and there are plenty of worthwhile reasons to get a poor night’s sleep — but it will be far easier to get back on track when the built and natural world both know the time.
