FRONTIERS A Matter of Time Living in circadian rhythm

Frontiers

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Salk Professor Satchidananda (Satchin) Panda runs his life like clockwork.

Most mornings, if he’s not traveling, he wakes up around 6 a.m. without an alarm. One of the first things he does is go out to his backyard to check on his provisions for wild birds. Their feeder is on an automatic timer that opens at 6:15 a.m., which is no surprise given that Panda’s research is on biological timing in animals and humans, and how disruptions to this timing can result in obesity, stress, metabolic disorder and possibly even cancer.

Having spent more than two decades unwinding the mysteries of biological clocks, Panda doesn’t just conduct circadian research—he lives it. An hour after Panda wakes and gets his daughter ready for school—which is enough time for his “sleepiness” hormone (melatonin) to wind down and his “wakefulness” hormone (cortisol) to begin ramping up—he has breakfast with his wife. (He looks forward to his daughter’s school district moving to a later start time, which will allow her to live in better alignment with her circadian rhythm.) His breakfast of homemade cottage cheese or yogurt, oatmeal and fruit yields enough complex carbohydrates and protein to keep his rising digestive enzymes busy and keep him fueled for much of the day.

At 8:00 a.m., Panda arrives at his lab, which is on the first floor of the Salk Institute, two levels below ground. Thanks to the ingenious “light wells” designed by architect Louis Kahn, the subterranean space gets plenty of natural illumination, which, according to Panda, is critical for helping to synchronize the cellular master clock in the brain and keep all the other body clocks on time.

These body clocks, or circadian rhythms, are 24-hour cycles that govern the behavior of living things, all of which evolved in the context of the planet’s alternating day/night pattern. Panda often refers to the “discipline of the clock,” an idea that biological activity—such as the production of proteins that help process food—rises during an animal’s waking period and slows during its resting period.

“The circadian clock is the body’s internal timing system, which interacts with the timing of light and food to produce our daily rhythms,” says Panda. “The best way to achieve optimal health is to live in accordance with the clock rather than fight it.”

While the body’s activities shift according to molecular timekeepers in almost every cell or organ, environmental influences, such as artificial lighting and constant access to food, can throw these circadian rhythms out of whack. Panda believes that understanding more about circadian rhythms—and how to manipulate them—could be the key to dramatically improving health.

And he has the data to back his thinking. As a researcher at the Genomics Institute of the Novartis Research Foundation in 2002, Panda was one of the discoverers of light-sensitive cells in the mammalian eye that function to set the master clock. That breakthrough earned his group and two others a place on Science magazine’s list of “Top 10 Discoveries of 2002.” And more recently, in a paper published in Science in February 2018, Panda and colleagues found that nearly 80 percent of genes in many tissue types and brain regions follow a day/night rhythm, with activity spiking in the morning and late afternoon and quieting down in the evening, around bedtime.

“The body cannot accomplish all its tasks at once, so functions such as digestion, growth and repair occur at certain times determined by the circadian rhythm,” Panda says. “This suggests that eating, exercising and sleeping during those times is more efficient and therefore better for our bodies and our health.”

The field of circadian science has only been gaining prominence as, increasingly, studies are finding links between circadian rhythm disruption and a wide range of health problems, from digestive ailments such as acid reflux to chronic diseases such as diabetes and dementia. Panda (who wears a specialized watch to monitor his own exposure to light and carefully tracks his eating, heart rate and motion) has seen firsthand the impact that changes in environment can have on one’s mood, productivity and health.

Circadian Clock

Because our early ancestors evolved to forage or hunt during the day and sleep at night, human biology is designed to support eating and physical activity during the day and cellular repair and cleanup at night, according to Panda. But refrigeration and other modern conveniences mean that many of us are eating during a window of 15 or 16 hours each day, giving our cells much more digestive work to do and not enough time for recovery and restoration.

Food timing: a simple change with drastic results

Unfortunately, many of the conveniences we enjoy in modern life seem to be at odds with our natural rhythms—in particular, exposure to artificial light and access to food around the clock.

The retinal cells that Panda and others discovered are sensitive to blue light—the kind emitted by many electronic devices and energy-efficient light bulbs—which means nighttime exposure tricks our brains into thinking it’s daytime, suppressing melatonin and making it hard to fall or stay asleep. One way to address this is to use the recent “nighttime” options in electronics that reduce blue light from screens. (Panda turns on his filter around 8 p.m. and avoids any harsh lighting at home.)

Another, perhaps more significant, factor disrupting our clocks is 24-hour access to food. Because our early ancestors evolved to forage or hunt during the day and sleep at night, human biology is designed to support eating and physical activity during the day and cellular repair and cleanup at night, according to Panda. But refrigeration and other modern conveniences mean that many of us are eating over the course of 15 or 16 hours of every day, giving our cells much more digestive work to do and not enough time for recovery and restoration.

In 2012, Panda, his then-postdoctoral researcher Megumi Hatori (now a researcher at Keio University) and colleagues published a trailblazing study in Cell Metabolism, in which they fed two genetically identical groups of mice the same amount of high-calorie food. The critical difference was that one group had 24-hour access to the food; the other was restricted to eating during an 8-hour window. The group with 24-hour access became obese and began developing signs of disease such as high cholesterol and insulin resistance. The time-restricted group, however, was lean and healthy—despite eating the same number of calories as the obese group.

Then, in 2014, Amandine Chaix, another postdoc in the lab (now a staff scientist), conducted a follow-up study with mice, in which she again observed an 8-hour time-restricted group, but also had groups restricted to 9, 10 and 12 hours. She got the same results: the mice with round-the-clock access to food gained weight and became unhealthy, while mice in the food-restricted groups stayed lean and healthy.

“We knew that the clock had an influence on metabolism, but we were really surprised to find that just restricting the timing of food could protect animals against weight gain and type 2 diabetes,” Chaix says.

More significantly, when she put the obese mice back on a time-restricted diet, they lost weight and regained their health, reversing course on high cholesterol, elevated blood sugar, high blood pressure and other markers of ill-health that lead to disease.

The groundbreaking studies have launched a whole new approach to improve human health with a relatively simple adjustment: restricting one’s calorie intake to an 8- to 10-hour window, which could confer a host of health benefits, including weight loss. On this regimen, one may occasionally go up to 12 hours of eating or may extend eating beyond 12 hours for a day or two in a week.

To find out whether humans can benefit in the same way, Panda’s team has been collecting data since 2015 about the eating habits of people all over the world via a mobile phone app called “MyCircadianClock,” in which people upload photos of everything they eat. Timestamps on the hundreds of thousands of photos submitted through MyCircadianClock reveal when the food was consumed. Aside from interesting tidbits about people’s eating habits (for instance, many people start with coffee and milk at 6 a.m. and end with a glass of wine or a bowl of ice cream at 9 or 10 p.m.), Panda’s team is seeing preliminary findings that indicate restricting food to within an 8- to 10-hour window benefits humans as well.

Even though the research in humans is early, Panda’s preliminary positive results have generated interest from fellow scientists, the media and the public across the globe. After a recent TV interview, media employees working behind the scenes swarmed Panda to learn more tips for doing the “circadian diet.”

“It is an appealing idea to lose weight and feel healthier not by cutting calories but just by timing your eating habits a little differently,” he says. “Everyone wants to learn more.”

Panda has written a book to share the health insights based on his own research and that of other circadian scientists with the public—The Circadian Code: Lose Weight, Supercharge Your Energy, and Transform Your Health from Morning to Midnight. In it, Panda recommends a window of 8-12 hours for eating. He favors an 11-hour window, which includes breakfast and dinner. He doesn’t eat lunch, because it makes him sleepy and less productive, which he, as the head of a lab of 40 people who travels frequently, can’t afford.

Food Timing

Right: Using tools such as smart watches and customized apps, the Panda lab charts participants’ exposure to light and food throughout the day.

For improved health, Panda recommends avoiding food for at least one hour after waking up as well as two to three hours before bedtime.

Benefits beyond weight loss

Restricting one’s calories and using other methods to match our circadian clock to a more natural rhythm has benefits beyond weight loss.

In January 2018, Panda and first author Gabriele Sulli published a paper in the journal Nature, describing how targeting the circadian clock in cancer cells could work as a therapy. Normal cells are used to producing and consuming nutrients only during specific windows of time determined by their circadian clocks. But cancers disrupt their cellular clocks so they can get nutrients all the time to support their unchecked growth. The team found that when drugs are used to reactivate the clock in tumors, cancer cells can’t survive. Healthy cells, however, are unharmed because they are already accustomed to the discipline of the clock, pointing to
a new possible target for cancer therapy.

Additionally, the Panda lab’s research has implications that could help shift workers—such as healthcare employees, members of the media and first responders—who often suffer much higher rates of chronic diseases due to disrupted sleep schedules. To explore this angle, the team received a $1.5 million grant from the Department of Homeland Security for a three-year study in collaboration with UC San Diego and the San Diego Fire Department to see whether restricting food intake to a 10-hour window can improve the health of firefighters, who—like many shift workers—have disrupted day/night schedules.

There is no shortage of projects involving circadian rhythms. Panda is collaborating with an MD/PhD scientist in training on a study of how circadian disruption in intensive care units affects patient health. Panda is also working with a visiting architect on developing guidelines to incorporate circadian-friendly lighting into building design.

After a packed day tackling his many projects, Panda usually leaves the lab between 4:30 p.m. and 6:30 p.m. to have dinner and time with his family. After some exercise and more work, he goes to bed by 11:00 p.m. at the latest. He has an eye mask to ensure complete darkness and keeps earplugs handy in case the coyotes from a nearby canyon get raucous.

Seven hours later, typically rested and refreshed from his disciplined routine, the circadian researcher begins the cycle again.

Tips to Lessen Jet Lag

With collaborations in Europe, Africa and Asia, Satchin Panda spends a lot of time traveling. In a recent two-month period, he jetted from his home base in San Diego to Chicago; Dallas; Nairobi, Kenya; Seoul, South Korea; Nashville; Denver; and Nagoya, Japan. Yet he rarely has jet lag.

Jet lag occurs when you travel across two or more time zones in a day. Most people’s circadian clocks take a day to adjust to each time shift so if you travel from one US coast to the other, for example, it may take you three days to fully adapt to your destination, says Panda. He recommends paying attention to your exposure to food and light to help adjust more comfortably to a new time zone. His tips (based more on personal experience than direct experimental data) include the following:

Cut your calories by half on travel days, when your physical activity will be significantly restricted.
For morning flights, don’t eat between the time you wake up and the time the plane takes off. Use your flight time to catch up on sleep. Many flights leave before 8:00 a.m., which means you are already sleep-deprived from getting up early or not sleeping well the night before your trip.
When sleeping on flights, wear earplugs and a sleep mask to get deeper sleep. Consider using a nasal breathing aid—getting more oxygen will help you sleep.
For afternoon flights, you will likely arrive at your destination at night. Don’t sleep on the flight, but do eat dinner if you are hungry. Once you arrive, wait until the following morning to eat.
If you arrive at your destination at night, avoid brightly lit places like grocery stores or drug stores that may affect your ability to fall asleep.
On very long international flights, try to sleep much of the time. This will help you avoid more than one meal and allow you to feel more rested.

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