Adapting Your Body Clock to a 24-Hour Society

Alexis Webb & Erik Herzog. American Scientist. Volume 105, Issue 6. November/December 2017.

“Aunt Lexie!!!” came the ear-piercing squeal from my niece as she ran toward my legs. I (Webb) smiled weakly, exhausted. My husband and I had been awake for nearly 20 hours, rising at the equivalent of the night before, local time, to travel to America from our home in London. How do you explain jet lag to a six-year-old? She was having none of it-our visit should mean that she had two of her favorite playmates at her disposal. But after little rest over the course of a day spent on planes and sitting in airports, my husband and I were desperate for some peace and quiet. Convincing a child your body still thinks it's on the other side of the Atlantic is nearly as difficult as convincing your body that it's not. Unlike our phones and other wired technologies, our bodies can't read the new time off the local network tower once we have arrived in a new location and adjust instantly.

Perhaps when my niece is my age, her activity tracker or some future device will be able to tell her brain the timing of her new environment, and jet lag will be a thing of the past. But so far, our access to technology has mostly been exacerbating the problem, not alleviating it.

Having studied biological rhythms and timing for decades, the two of us (Webb and Herzog) are usually the go to people for friends and colleagues seeking advice on how to beat the transatlantic travel blues. Our basic tenets include: Spend time outside, preferably in direct sunlight, when you arrive. Eat a meal on local time. Try to stay awake until your normal bedtime where you are, not where you arrived from. For most people, flying west, which prolongs your wake-sleep rhythm relative to normal, feels easier than flying east. Although you may find yourself unable to sleep in the early morning hours and flagging at the end of the day, flying west tends to be kinder to the body. It's not always so easy to follow these rules, however, and it gets harder still as our daily routines keep changing in ways that can sacrifice well-being.

The feeling of jet lag, of being just a bit off and out of sorts, arises because of a discrepancy between internal time and the environment. In the brain sits a biological clock that coordinates the regular daily timing of nearly all of the body's processes. This clock is set or entrained to local time through light input from the eyes. The change in time experienced when people travel across time zones cannot be processed instantly by the clock in the brain; there is no watch hand to wind to a new time. The internal clocks must readjust to the new environment through experience of the new day-night cycle.

These days, people don't need to get on a plane to experience conditions that are at odds with internal rhythms. Modem 24-hour lifestyles have similar effects because society no longer relies on the day-night differences in external conditions that human bodies evolved to track and set processes to. The everpresent access to food, technology, and, most notably, electric light means that people are regularly exposed to stimuli that are not coordinated with the body's internal time. Couple this development with the constraints of the standard working day, which may necessitate waking before preferred morning rise time, and the clash of body time with environmental time is continual. Researchers have described this phenomenon as social jet lag- going through daily life at odds with the circadian rhythm-which can have profound consequences for health.

The good news is that advances in research and technology are providing better ways to track and train the body dock to cope with modem living. At the same time, scientists are improving their understanding of possible targets for drugs, making better use of data from wearable devices, and bringing together citizen scientists to examine real-world behavior, which can be vastly different from what is observed in the controlled conditions of the laboratory. New technologies that are changing our lifestyles and challenging our clocks will also be able to provide exquisite details about our biology, leading to solutions never realized before.

Entrainment in a Modem World


The modem world increasingly makes possible or even demands nighttime activity. Thanks to social media and other modes of connectivity, people from anywhere in the world can see what our planet looks like from the International Space Station at any time and see that the surface of the Earth looks much different than it did 100 years ago. Aside from the changes to the landmasses, oceans, and ice sheets, the area now covered by electric lights, which resemble millions of fireflies shining out into darkness, is immense. Although large parts of Africa, South America, and Asia still face night in relative darkness, North America and Europe appear as glowing lattices of cities and towns.

In contrast to the circumstances of previous generations, the end of the day no longer means the end of work and activity. Thanks to the inventions of Nikola Tesla and Thomas Edison, humans can remain active at night. One of those lights below is a hospital in Manchester, where nurses and doctors are working their rotating overnight shift. Another is an all-night fast-food restaurant in Atlanta, where employees serve burgers and greasy fries to patrons into the wee hours. More than 20 percent of the workforce in industrialized countries has irregular, rotating, or unstable shifts. Not only are people working at all hours, they have constant access to technology, information, and, well, stuff. Since the advent of Amazon.com in the 1990s e-commerce has boomed; more than half of all purchases are now made online, where we have 24-7 access to shopping. And thanks to this change toward a retail-focused economy, more people are working jobs with antisocial hours. Modern society no longer requires citizens to rest and reset. The world is nonstop, and the consequences are beginning to show.

Evolution has not caught up to these changes in day-to-day life. Humans, as well as nearly every other organism on the planet, are adapted to the 24-hour rhythm of light and darkness that arises from the spinning of Earth on its axis. Fighting against this finely tuned clock, which is responsible for coordinating essential daily processes, such as metabolism and hormone release, has enormous implications for human health.

Nurses working the night shift at a hospital have an 8 percent greater chance of developing breast cancer, and that chance continues to rise for every year that an individual works a rotating night shift. Nighttime fastfood employees and their hungry customers are fighting against the body's metabolic rhythms by eating food around the clock, including at times when the body expects to be at rest and fasting. This kind of metabolic jet lag is linked to obesity, which brings with it a whole host of additional health problems. On the whole, society is working more and sleeping less, increasing the risk for depression and anxiety issues. Such disobedience to the circadian clock, a behavioral problem arising from changes in modern living, is adding to the growing financial strain on health services worldwide. In the United States alone, an estimated $14 billion per year is spent on health care for sleep disorders, according to the U.S. Institute of Medicine Committee on Sleep Medicine and Research.

The word circadian, from the Latin circa diem, meaning "about a day," describes the body's near 24-hour internal clock that is set to the local environment. This clock is intrinsic; it will persist even in constant conditions that do not change, such as in a cave or deep in the ocean. Modern working environments are quite different from conditions in a cave, but in either setting the body must use information from the sensory system to time the intrinsic circadian clock to the environment-put simply, to tell whether it is day or night.

Specialized cells in the retina, called intrinsically sensitive retinal ganglion cells, are primarily used for light detection rather than for image formation. These nerve cells connect the eyes to an area at the base of the brain within the hypothalamus called the suprachiasmatic nucleus (SCN). Scientists have studied this structure for decades-first observing that animals with lesions in this area lose all behavioral rhythms. Pioneering transplantation studies led to the conclusion that the SCN structure is both necessary for generating daily rhythms and sufficient for providing them.

The rhythm provided by the SCN is not exactly 24 hours in length. Depending on the organism, it can be slightly longer or slightly shorter than 24 hours, with humans falling into the former category. Light detection through the eyes sets the internal rhythm to the daynight cycle. The size of the adjustment needed is flexible; depending on the latitude and the time of year, humans experience different lengths of day and night. Therefore, our internal clock must change its relationship with the light cycle to be awake and asleep at the optimal times. This offset is otherwise known as the phase relationship between the body clock and the environment, signifying how internal time must speed up or slow down to fall in line with the daily experience of light and dark. An added complication for many people is that the times they need to be awake and asleep change throughout the week and may be at odds with what is happening in the environment.

Changing the body clock to the right phase relationship underlies the process of entrainment. This process is at the heart of improving circadian fitness and is likely the reason that more and more people will struggle with their health. Sunlight is the most powerful entraining signal for the body clock. But in the modem era of electricity and nonstop access to information, it's the light received via a computer screen after dinner or a smartphone screen before bed that counteracts the day-night cycle provided by the Sun. Too many constant inputs are in conflict with the daily biological cycle we evolved for.

Historically, there have been two conceptual models that explain the entrainment that takes place to synchronize the internal and external rhythms: the discrete model and the continuous one. To understand the difference, imagine two cyclists going around a circular track-they are cycling at the same speed, but there is a distance between them. This distance represents the phase difference between cyclist 1 (the environmental clock) and cyclist 2 (the internal clock). In the discrete model, a light stimulus (or other entraining signal) given at a certain point on the route around the track allows cyclist 2 to immediately overcome the distance and jump to a new point on the track, the same point as cyclist 1, so that the internal clock is in sync with the actual environment.

Essentially, according to the discrete model, light can immediately shift the internal clock to the phase of the environmental light-dark cycle. The continuous model argues that an entraining stimulus would cause cyclist 2 to increase or decrease her speed over the subsequent cycles until she is at the same point on the track as cyclist 1. This process happens over multiple loops as the internal clock is continuously adjusting to fall in line with the environmental cycle. Although aspects of both discrete and continuous entrainment are still favorably regarded in the literature today, these two models of entrainment have failed to unify the field. Recently, an alternative theory has been proposed, which postulates that changes in how the circadian system integrates light signals at different times of day allows it to to the environment.

In both the continuous and discrete models, depending on what time the light stimulus arrives, the extent of the light shift varies. For example, light exposure during the day has little effect on the intrinsic clock. This idea seems intuitive-if the purpose of light is to shift the clock, then either limiting exposure to the light, or in the case of the circadian system, limiting when light has a shifting effect, would be beneficial. Plotting the change in the phase of the internal clock relative to the external environment based on time of light exposure, otherwise known as the phase-response curve, shows that the biggest shifts occur at two points: just after dusk and just before dawn.

Bright light exposure after dusk has the ability to delay the clock, shifting activity later, as if one were experiencing a longer day. Light exposure before dawn has the ability to advance the clock, shifting activity earlier to start a new day. Night-shift workers face light exposure that can both advance and delay their clocks; rotating-shift workers struggle between "regular" and shifted schedules, never successfully entraining to either. Models simulating phase-response curves based on data from the underlying circadian rhythm can now help frequent travelers predict when they should be exposed to light to best entrain their body clocks to their current local time {see sidebar on preceding page).

Although most of the world won't be attempting to intentionally shift circadian rhythms in this way, it is the transitions in light at dawn and dusk that help entrain the slightly longer internal rhythm to the 24-hour day-night cycle of the environment. Studies have shown that two light stimuli, one when diurnal activity starts and the other when it stops, provide enough time information to the circadian system to set it to the environmental rhythm.

How much light is necessary to shift and set the body dock? Although bright sunlight with an intensity measured at 100,000 lux is most efficient, recent studies by researchers at Harvard Medical School have shown that even the light emitted from the LED (lightemitting diode) screens of smartphones and tablets, when seen before bed, is enough to delay the circadian clock and disrupt sleep. Indeed, the light-sensing retinal ganglion cells that project to the SCN are particularly sensitive to the blue light from these screens.

Avoiding phone use at night to prevent body clocks from shifting is not the only option; technology has been developed that can purposefully block the blue light from being emitted (see sidebar on preceding page). On an overcast day, the eyes still receive around 2,000 lux. But the illumination level of indoor lighting is often much lower, and can be as low as 50 lux. Limited bright light -exposure for elderly patients in care homes could be one reason for the disrupted sleep and activity rhythms observed in those populations.

Can We Entrain Faster?


Being in tune with the environment is a boon for organisms, not only for 'the early bird that gets the worm," but also for nocturnal animals who time their activity cycle to minimize predation and improve survival. As mentioned in the previous section, the strongest entraining signal for the circadian clock is light. Unlike the brains of birds, human brains cannot experience light directly through the skull and must rely instead on a specialized part of the visual system. Indeed, research over the past 20 years in humans (and mice) lacking parts of the image detection apparatus of the eye- the rods and cones-showed that they still maintain daily rhythms; that research contributed to the discovery of those specialized light-detecting ganglion cells crucial for entrainment.

Many people, such as parents of young children and business travelers, would surely benefit from an internal clock that can be set to local time faster. The nurse and the fast-food worker who are forced to work against their daily rhythms would be able to improve their health with a clock that was easier to shift and reset. Can circadian biology provide any insights?

Bad news first: There are lots of gimmicks that are not based on sound science. Probably one of the most infamous published studies in the field claimed that light exposure to the back of the knees improved entrainment following a long-haul flight-a conclusion based on a faulty correlation. There are no photoreceptors located behind the kneecap. Plenty of other proposed timeshifting quick-fixes exist that haven't been published in scientific journals, but they still are sometimes promoted in the pages of in-flight magazines or newspapers. Many of these treatments, such as therapy with melatonin or benzodiazepines, are designed to promote sleep, but they won't necessarily aid in entraining your circadian rhythm to a new external time. In addition to exposure to light, one of the other rhythmic signals that may help realign the clock faster is shifting meals to local time at the destination as soon as possible.

More recent research has examined the effects of chemicals, such as kinase inhibitors or DNA damage regulators, on the behavior of the SCN, specifically to find out whether exposure to them can speed up the adjustment to a new time. A pill that could help beat jet lag is likely years away, but studies suggest that certain drugs may be able to influence the timing of brain cells or their ability to respond to entraining signals. Human SCNs are comprised of tens of thousands of neurons, electrically active cells that can send timing information to the rest of the brain and body. These neurons are themselves rhythmic; their firing is cyclic over a 24-hour period and it is light input (and the neurochemicals released by those light-receiving cells) that influences the timing of activity.

In addition to maintaining their timing relative to the outside world, SCN neurons are also set in time with one another. Imagine a symphony of musicians. They may not play all at once, but an individual section must keep time relative to the others, with the conductor setting the overall pace of the performance. Light input communicates external timing to the conductor in the SCN, who then relays this information to the rest of the neurons, and in turn, to the rest of the body. Many studies have tried to identify the roles of different areas and cells types in the SCN and to elucidate how the symphony comes together.

When neurons in the SCN fire, a neuropeptide, vasoactive intestinal poli/peptide or VIP, is released. Under normal conditions, VIP plays an important role in keeping the cells of the SCN synchronized to the same beat. Researchers in one of our (Herzog's) labs have shown that high concentrations of VIP, however, can throw the SCN symphony into disarray. This lack of synchrony in the rhythms may be beneficial when it comes to speeding up entrainment.

To explain how this role might work, we collaborated with computational scientists, who built a mathematical model of the circadian rhythm in an SQM neuron. Our model predicted how desynchrony could make entrainment happen faster. In the model, neurons responded to high doses of VIP with a behavior described as "phase tumbling." Essentially, lots of VIP produces a transient phase decoupling across the cells, shifting them in time relative to one another. This dispersion likely occurs due to molecular variability or noise in the levels of gene activity and protein amounts in individual cells-evidence our lab has also observed. In the model, the shifted cells are also quicker to readjust and entrain to new times, suggesting that high VIP levels might help alleviate jet lag.

To test this idea, researchers in our lab recently measured the rhythmic activity of mice provided with running wheels. They simulated jet lag for the mice by shifting the light schedule to either advance or delay the environmental signal by six hours relative to the previous schedule. Researchers examined when the mice would be active on their running wheels following the shift. Mice that received injections of high concentrations of VIP in the area around their SCN were able to entrain faster to the new schedule compared with control mice that received injections of saline instead. Because VII? is released from the neurons that receive input from light-sensing cells in the eyes, a good dose of bright sunlight may help trigger phase tumbling in our SCN and hasten readjustment to a new time.

Researchers have also been examining whether the introduction of other compounds could improve entrainment. Screens of libraries of small molecules, including primarily synthetic compounds that can bind to genes and proteins that could produce or lead to enhanced shifts, is a high-throughput way of identifying candidates. A future for improving entrainment may rely on a combinatorial approach. By using light together with drugs, timed meals, and other stimuli, humans may be able to better tune and enhance the phase relationship between their internal and external timing.

Technology to Improve Entrainment


The past 10 years have seen an explosion in constant connectivity by way of mobile devices and other technologies. In addition to listicles and cat pictures, the internet now contains vast amounts of data generated by the population, including information about sleep and wake patterns, food intake, and location. This era of quantified self, collected through activity trackers and apps, means that there are more data than ever before about people's daily lives. Some fast-food workers, for example, might have a Fitbit that measures their steps, exercise, sleep, and heart rates. They could use this wealth of information to make better and more informed decisions about their daily behavior. Activity trackers encourage wearers to think about how much and what they do on a daily basis-and also about when they are doing each of their routine activities. Those who want to learn more about their circadian behavior now have access to apps and websites offering more information. Scientists also are utilizing the internet to connect with other members of the public who would like to contribute to research. These citizen scientists can use mobile technology to generate and share data with researchers, essentially turning the world into a giant laboratory.

Developers of research-based apps have empowered people to become part of the scientific process of understanding their biology. Using an app to track behavior can provide a window into daily life in the real world, without the constraints of a controlled environment in the lab. These sorts of data are particularly useful to observe the changes seen in 21st-century lifestyles compared with lifestyles of 50 or even 100 years ago. Large-scale surveys such as the Munich Chronotype Questionnaire, whose questions place individuals across a distribution based on the midpoint of when they'd prefer to be asleep, have been important in collecting anecdotal evidence about the when, where, and how of people's sleep habits. But with activity trackers, the scale of raw data that we have about people's daily behavior from around the world is enormous. Apps that track sleep and wake times, food intake, and other aspects of biological rhythms, such as My Circadian Clock and Entrain, have already provided new information about obesity and recovery from jet lag (see sidebar on page 349). Now and in the near future, researchers could use such apps in combination with other personal data, such as medical records and genetic predispositions, to paint a more detailed picture of how the circadian clock contributes to overall human health as well as disease risk.

The challenge now is figuring out how to spread the word to people about the effects of a healthy circadian rhythm on conditions such as obesity, cancer, and mental health, and how best to encourage more people to examine the data they generate to discover how their rhythms could be improved. Until better solutions for circadian dysfunction exist, those of us prone to late-night Netflix streaming or scrolling through our Instragram feed before we tum out the light can take steps to be healthier by acknowledging our circadian rhythms and trying to minimize disruption to our clocks.

A couple of straightforward changes can make a marked difference in alleviating entrainment problems: removing all technology from the bedroom and ensuring that some time is spent outdoors every day. An instantly adjusting body clock, aided by wearable technology and apps, may someday be possible. But achieving it will require more research to understand the ways in which biology and the rhythms of modem life can work together in harmony.