The Complete Guide to the Science of Circadian Rhythms


HIGHLIGHTS

→ Maintaining consistent and healthy circadian rhythms may help improve overall health and prevent chronic diseases.

→ Think beyond sleep: Circadian rhythms are influenced by eating, exercise, and other factors.

→ Learn the idiosyncrasies of your own rhythms, your “chronotype,” then adapt them to the best practices indicated by scientific research.


This story is focused on the science of circadian rhythms, the 24-hour physiological patterns that most organisms, including humans, follow each day. This article is intended to review the current science on the topic and not principally to offer advice, though we do present potential lifestyle modifications. It is not an exhaustive review of the field of research, and we will continue to update it as more science emerges.

As always, any health advice should be discussed with a healthcare practitioner before incorporating it into your routine.

The Basics: What Is a Circadian Rhythm?

Picture a plant trying to perform photosynthesis at night: Without light, it’s a short drama. “Plants are dealing with life and death,” said Sally Yoo, assistant professor in the Biochemistry and Cell Biology Graduate Program at the University of Texas Health Science Center at Houston (UTHealth), somberly. “If they don’t follow circadian rhythms, they’ll die.” For humans, the prognosis would be slightly less bleak. “Even if you deleted the clock gene [an important gene regulating circadian rhythms], you wouldn’t die immediately,” Yoo said. “But you will suffer.” Likely problems? Constant psychological confusion and heightened risk for chronic disease, among other things. Life’s tough when everything’s out of sync.

Yoo’s colleague, Jake Chen, an assistant professor in the same department, put it another way: “In our life, we say, ‘Timing is everything.’ But that’s an exaggeration. It is not, however, an exaggeration to say, ‘There is an optimal time for everything.’ In our body, it’s the same. Within individual cells and within each tissue or organ there’s a time for every physiological process. The circadian clock is the master mechanism, or timer, to make sure that everything runs smoothly and according to plan. That is a fundamental function.”

Chen and Yoo study circadian rhythms, the 24-hour physiological patterns that most organisms, including humans, follow each day. These rhythms are hardwired from millions of years of the world spinning around. The system is old, robust, flexible. It’s the product of an organism’s internal biological clocks and environmental cues — most notably, the sun, but also many other factors —which govern our behavior, hormone levels, sleep, body temperature and metabolism.

The so-called “master clock” governing human circadian rhythms is the suprachiasmatic nucleus (SCN), a pair of cell populations packed with genes that carry out this function (including Clock, Npas2, Bmal, Per1, Per2, Per3, Cry1, and Cry2), located in the hypothalamus portion of the brain. While molecular clock genes also exist elsewhere—the kidney, liver, pancreas, muscles, so on—the SCN acts as the chief executive officer, instructing the rest of the body to stay on schedule and figuring out how to incorporate cues from the environment. (For a brief digression, see how exactly the SCN works in an interactive feature by The Howard Hughes Medical Institute.)

As we’ll discuss later, being good to our natural rhythms improves daily physiological and psychological function—and ultimately short- and long-term health. Reducing the wear and tear on the clock keeps it fresh, maintaining what Yoo called “a robust clock” later in life. Chen was even more emphatic: “I cannot emphasize enough how important the circadian rhythm is for prevention of chronic diseases,” he said. “And for long term benefits toward healthspan and eventually lifespan.”


Meet the Experts

Scientist: Zheng “Jake” Chen

Education: Ph.D., Columbia University, NY, Postdoctoral Fellow, The University of Texas Southwestern, Dallas, TX

Role: Associate Professor, Biochemistry and Cell Biology Graduate Program, University of Texas Health Science Center at Houston

Recent Paper: The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome.

Area of Study: Small molecule probes for chronobiology and medicine.

Scientist: Seung-Hee “Sally” Yoo

Education: Ph.D., Korea Advanced Institute of Science and Technology

Role: Assistant Professor, Biochemistry and Cell Biology Graduate Program, University of Texas Health Science Center at Houston

Recent Paper: Period2 3′-UTR and microRNA-24 regulate circadian rhythms by repressing PERIOD2 protein accumulation. Also, Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems.

Area of Study: Fundamental cellular mechanisms in circadian rhythms and deciphering physiological and pathological roles of the clock.


The History: Establishing the Fundamental Biology of Circadian Rhythms

The first thing to know about the study of circadian rhythms, also known as chronobiology, is that with few exceptions all organisms on the planet follow a circadian clock. From daffodils to sparrows, zebras to humans, everything under the sun follows the pattern of the sun. In 1729, French scientist Jean-Jacques d’Ortous de Mairan recorded the first observation of an endogenous, or built-in, circadian oscillation in the leaves of the plant Mimosa pudica. Even in total darkness, the plant continued its daily rhythms. This led to the conclusion that the plant was not simply relying on external cues, or zeitgebers, but also its own internal biological clock.

Two hundred years later, in the mid-20th century, the world of modern chronobiology blossomed. The field benefitted from contributions from a number of scientists, notably Colin Pittendrigh, the “father of the biological clock.” Pittendrigh studied the fruit fly Drosophila and shed light on how circadian rhythms entrain, or synchronize, to light-dark cycles. Jürgen Aschoff, a friend of Pittendrigh, also studied entrainment modeling, although they reached different conclusions about the manner in which entrainment occurs (parametric versus non-parametric, which you can read more about here and here). John Woodland Hastings and his lab also made important foundational discoveries about the role of light in circadian rhythms by studying luminescent dinoflagellates, a type of plankton. Erwin Bünning, who studied plant biology, also contributed foundational research in entrainment modeling, describing the relationship between organisms and light-dark cycles.

The next phase of chronobiology discovery began to articulate the specific molecular and genetic mechanisms of circadian rhythms. This came from the work of Ron Konopka and Seymour Benzer, who in the early 1970s aimed to identify specific genes that controlled the circadian rhythms in fruit flies. Konopka and Benzer are credited with discovering that a mutated gene, which they called period, disrupted the circadian clocks of the flies. This was the first discovered genetic determinant of behavioral rhythms. Jeffrey C. Hall, Michael Rosbash and Michael W. Young expanded Konopka and Benzer’s work by successfully showing how the period gene worked on the molecular level. Hall, Rosbash and Young—who were awarded the 2017 Nobel Prize in Physiology or Medicine—isolated the period gene, and then showed how the clock system worked on a molecular level.

Jumping from fruit flies to mice, Joseph Takahashi and his team discovered the mammalian clock gene in 1994—appropriately dubbed clock—and characterized it as an “evolutionarily conserved feature of the circadian clock mechanism.” This gene discovery, along with the body of work by Hall, Rosbash, Young and the scientist Michael Greenberg, led to a watershed in chronobiological knowledge. Within a few years, the genes informing circadian rhythms in lower organisms were largely worked out.

Things have progressed steadily ever since, and, many of the findings in fruit flies and mice have shown remarkable conservation across species, meaning that there are analogous circadian genes that control the rhythms of more complex animals, including humans.

The Current Research: Articulating the Role of Circadian Rhythms in Human Health and Disease

It’s important to note that the biology of circadian rhythms is incredibly complex—there are multiple scientific journals dedicated to the field of research—and as a result our understanding of the role biological clocks play is mostly a result of animal studies and human epidemiological studies. The experiments in lower organisms help articulate the molecular and genetic mechanisms at play, and then scientists can look at, say, how sleep disruption leads to increased incidence of type 2 diabetes, obesity, and cardiovascular disease.   

Indeed, one area of study that’s especially promising is sleep. Scientists are now implicating a lack of sleep and the consequent disruption of circadian rhythms in the development obesity and depression, as well as most chronic diseases. Studies even show that a lack of sleep may have unexpected side-effects like not being able to read facial expressions.

The understanding of how circadian rhythms work has also expanded well beyond interaction with the light-dark cycle. “We have social cues, eating cues, and exercise or activity cues—it’s very diverse,” Yoo said. The rising and the setting of the sun is still the primary influence on circadian rhythms, but other systems have steadily grown in scientific inquiry. A large body of work has demonstrated that diet is a key extrinsic cue interacting with the intrinsic clocks, including Dr. Satchidananda Panda’s work on time-restricted feeding, or how the time of eating impacts health. (Endpoints covered Panda’s research at length, which you can read in The Complete Guide to the Science of Fasting.)

Overall, it is now clear that circadian rhythms perform a systemic role to orchestrate all aspects of physiology in our body, including vital organ functions, metabolism, immunity, cognition and more. Yoo’s research has been expanding the field, partnering with a chronic pain specialist to study the rhythms of pain in patients. Work is also being conducted on the role of the light-dark cycle and disruptions in circadian rhythms by jet lag on cancer growth. Such studies of circadian rhythms under normal and disease conditions are teaching us important new insights that can be harnessed for lifestyle changes (when to eat, how much to sleep) and for discovering drugs that can help modulate circadian rhythms. And there is plenty more research to be done in virtually all aspects of human health and disease.

 

The Takeaway: Why Does Awareness of Your Circadian Rhythms Matter?

An awareness of the fundamentals of circadian rhythms can have both short- and long-term effects on health. “Lifestyle changes are the best gift you can give yourself,” Chen said. “If you manage your lifestyle, medicine and technology could all be secondary for a long time during your life.” In the short-term, animal and human studies suggest that following lifestyle practices that support healthy circadian rhythms could support cognition, alertness, coordination, cardiovascular efficiency, the immune system, consistent bowel movements, and sleep. In the long-term, there is evidence supporting reduced risk of chronic diseases and an extended healthspan. “It’s a chronic process to maintain it,” Chen said. “The effects may not manifest in a few days, but over time, the benefits will be enormous.”

So how can you best pursue a lifestyle in sync with your circadian rhythms? The first thing you need to do is pay attention to your natural rhythms. Circadian rhythms, while generally built on the same foundation, vary from person to person because of age, genetic, and environmental differences. Morning people like mornings better. Night people like nights better. Paying attention to our natural inclinations, also known as our individual “chronotypes,” allows us to incorporate the best practices from circadian rhythm research while also acknowledging that there’s no one-size-fits-all approach.

The second best thing you can do for yourself is establish a consistent routine—and that means seven days per week. Yoo discussed the idea of “weekend jet lag,” (or “social jet lag”) where people throw off their rhythm with atypical habits, for example, eating and going to sleep later, waking up later, and exercising at different times of the day. This can cause the same kind of negative effects as changing timezones. The closer and more consistently you can keep your routine, the better your body will run on that routine.

Lastly, incorporate the research, which we present in detail for sleep, eating, and exercise, below. Many of the lifestyle changes the studies suggest—for example, that eating right before sleeping is a bad idea—have little downside. Eating bigger meals earlier in the day and smaller meals in the evening is easy enough to try. Likewise, sleeping on a standard schedule, with seven to eight hours of sleep per night, has no apparent downside. At worst, you’ll feel rested, and at best you’ll improve your prospects for a healthy life.

Best Practices: Some Sleeping, Eating, and Exercise Tips for a Healthy Lifestyle

Sleep: The most important thing you can do is keep your sleep and waking times consistent and get enough sleep—seven to nine hours is usually considered the right amount for adults. At this point the scientific research on not getting enough sleep or having disruptive sleep is conclusive: It has a negative impact on mood, focus, cognitive function, and ultimately is linked to chronic disease. What’s more, some scientists suggest that circadian misalignment caused by social jet lag may be a widespread phenomenon in the western world contributing to health problems.

So when should you sleep? Typically the body begins to secrete melatonin around 9:00 p.m. This is the trigger to shut things down and go rest. Melatonin secretion ends around 7:30 a.m., and during the day, there is virtually no melatonin in the system. Working around that general window, adjusting for personal preferences based on your natural inclinations, is key for avoiding sleep fragmentation (waking throughout your sleep) and for maintaining optimal health.

Finally, light is a factor. The light-dark cycle no longer is the only influence on our system, since we now encounter artificial light constantly—but it still plays a primary role. Getting plenty of natural light early in the day and avoiding unnatural light (blue light from screens, for instance) in the evening will support circadian alignment.

Key Takeaway: Get plenty of sleep, and keep your sleep and waking timing consistent seven days per week. If you have sleep debt, start paying it down now, before it compromises your long-term health.

Further Reading:

The Circadian Clock and Human Health

Melatonin: both master clock output and internal time-giver in the circadian clocks network

Shift work and the assessment and management of shift work disorder (SWD)

Eating: Generally speaking, studies suggests that eating your calories earlier in the day is better. Try to have your last meal be a smaller intake of calories, and have it occur well before your bedtime. If you can wrap things around 6:00 p.m. or 7:00 p.m. and give your body 12-14 hours to rest and restore, you may see short- and long-term health benefits.

Part of the reason is that, at night, your liver clock will shut down. It stops producing enzymes to convert calories to energy; it’s producing enzymes to store energy. If you load in a bunch of food, you’re making it work overtime—and it’s going to store more than burn.

The other significant lifestyle decision you can make (beyond eating a healthy diet) is to restrict the window during which you eat. While the data thus far is restricted to animal studies, Dr. Panda’s work suggests that “time-restricted feeding” is an easy and potentially beneficial lifestyle change. “What is optimal depends on someone’s goal,” he says. “But if the goal is to improve overall health, then 8-9 hours might be better to begin with, but in terms of sticking with it long term, maybe 10-12 hours is practical.”

Takeaway: Eat more earlier in the day, rather than later. Eat within a 10-12 hour window.

Further Reading:

Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan

Circadian integration of metabolism and energetics

The night-eating syndrome: implications for severe obesity

Exercise: While some research suggests that anaerobic performance peaks in the afternoon, there doesn’t appear to be a scientific consensus on the relationship between circadian rhythm and exercise—except that there are in fact molecular clocks in skeletal muscle. And like light and eating, when you exercise likely plays a role in maintaining healthy rhythms.

Takeaway: Exercise often, and save your anaerobic activities for later in the day.

Further Reading:

Sports performance: is there evidence that the body clock plays a role?
The effect of training at a specific time of day: a review
Circadian rhythms, skeletal muscle molecular clocks, and exercise

If You Remember One Thing: Final Thoughts on Circadian Rhythms

Distilled down, the research on circadian rhythms is fairly straightforward. “Your body clock is designed to burn during the day, then restore or reprogram during the night,” Yoo said. The better in sync to that cycle you are, the less wear-and-tear on your circadian clock. While the clock is resilient, consistent disruption can cause long-term health issues.

“When you are young, your body can take it,” Yoo said. “But it doesn’t mean that it’s completely okay. It’s like mileage: You’re using up your mileage by doing that kind of [arrhythmic] activity, and that will create problems when your body clock is no longer robust.”

You’re not shaving off five years of your life from one late night of eating and drinking, but the clock is there to protect and minimize the disruption to our physiology. Be kind to it and you may well notice the benefits to your health.

Jeremy Berger is the Director of Content for Elysium Health, a consumer health company that translates advances in science and technology into clinically-validated health products. He works with a team of writers and scientists to create stories that make sense of complex topics in health and science. Read more at Endpoints and follow on Twitter @ElysiumHQ.

The Complete Guide to the Science of Circadian Rhythms