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Biological Circadian Clocks and Health Sciences Yu Tahara, Assistant Professor (December, 2015)

  • Yu Tahara, Assistant Professor (December, 2015)

A Circadian Clock Found Throughout the Body

Our body has a system that measures a cycle of approximately 24 hours. This is called a circadian, or biological, clock. It is a physiological mechanism that controls a variety of functions, including the sleep-arousal rhythm, hormone secretion, and daily variations of body temperature. It play an important role, especially in maintaining an organism’s homeostasis.

In the 1980s, it was already known that a clock that controls this circadian clock, or the “central clock,” so to speak, existed inside the brain (the hypothalamus). However, the elements that held the key to the clock were as yet unknown. Later, studies on the circadian clock picked up speed after a mammalian clock gene was discovered in 1997. At this point, about 20 to 30 kinds of clock genes have been discovered. It has also been revealed that circadian clocks are not only located inside the brain, but also exist in all the organs and cells of the body as “peripheral clocks.” For example, each clock found in the liver, kidney, lungs, and other parts of the body produces a steady, 24-hour rhythm. The central clock, meanwhile, serves as the “master clock” to oversee and control the time marked by the peripheral clocks. This is the mechanism by which a biological circadian clock works.

The Importance of Biological Clock Research

An experiment using mice has revealed that the subjects show depression-like behaviors if placed in abnormal light environments, such as 7-hour cycles instead of 24-hour cycles. Individuals with either no clock gene or a mutated one develop abnormalities in their sleep-arousal cycle, become obese, and/or develop diabetes, cardiovascular disorders, etc. There are also many factors in our daily lives that can disrupt our circadian clock, such as time differences due to travel, working night shifts, etc. There have also been reports that working at night raises the morbidity rates of cancer and lifestyle diseases. In other words, there is a possibility that disturbances of the circadian clock may lead to a variety of illnesses.

The fact is, the clock gene does not necessary produce a 24-hour rhythm accurately. In an experiment in which a group of subjects were made to live in an environment where they had no clock and could not discern changes in outdoor brightness, their sleep and arousal cycles produced a lag time of about 10 minutes each day, on average. We adjust our circadian clocks as we live our daily lives. For example, it is well known that, for humans, morning light is extremely effective, and, likewise, meals are also believed to be an important stimulation.

Establishing a Method of Measuring the In Vivo Bioluminescence Rhythm

I established a new method of measuring the circadian clocks of mice peripheral tissues using the luminescence of fireflies. For this technique, I used a mouse with firefly luciferase integrated into its Per2, a representative circadian gene, and an in vivo imaging system mounted with a high-resolution CCD camera. By anesthetizing this mouse and taking a photo from above, it was possible to visualize the luminescence of its internal organs. Taking such photos repeatedly for 24 hours allows us to measure the daily circadian variations of the clock gene’s actions, as the luminescence rhythm. This luminescence measurement method was originally used in cancer research, but for this study, I applied it to measure the circadian clock. This made it possible to easily measure the clock genes that are expressed in the peripheral tissues (liver, kidney, and submandibular gland) while keeping the mouse alive.

Fig. 1: A method of measuring in vivo luminescence rhythms in which the expression of the clock gene can be measured in living mice

A New Field of Learning Called “Chrono-Nutrition”

I used this new measurement method to investigate the changes in the expression of clock genes by administering caffeine to a mouse. The results showed that caffeine prolonged the circadian clock cycle, and that it delayed the peripheral clock, especially if taken in the early evening or night.

Moreover, in our previous experiment using mice, we revealed that postprandial insulin secretion was important for resetting the circadian clock of the peripheral tissues, and that ingestion of feed after extended fasting in particular produced a strong resetting effect. It also was revealed that fish oil containing long-chain fatty acids such as DHA and EPA had insulin secretion promotion actions, and reinforced the circadian clock resetting effect of a meal.

Based on these results, our laboratory proposes a concept that we call “chrono-nutrition,” the investigation of what, how much, and when to eat.

Stress and Circadian Clocks

We also studied how the loading of stress changes a mouse’s circadian clock using an in vivo imaging system. For three consecutive days, we applied stress to a mouse by restraining it in a small physical space for two hours once a day, and measuring the changes in the luminescence pattern of its peripheral tissues (liver, kidney, and submandibular gland). The results showed that physical and psychological stress in the form of restraint was a powerful stimulant, strong enough to alter the time of circadian clocks. We also obtained the interesting finding that the actions of stress varied significantly depending on the time zone in which stress is applied.

Fig. 2: Timing of stress loading and its influence on the circadian clock

Similar results have also been obtained when applying other types of stress, such as forcing a mouse to face an aggressive and large mouse on the other side of a divider (social phobia) or leaving a mouse on top of a small stage (fear of high places).

The Eventual Application of Circadian Clocks for Use in Humans

Research on circadian clocks is being conducted all over the world, and Japan is at the cutting edge. Professor Shigenobu Shibata, my mentor, is a researcher who was the first in the world to report that a central clock produces a 24-hour rhythm of neural activities. The discovery of Bmal1, a leading clock gene, was also the achievement of a Japanese researcher. There are numerous laboratories that study circadian clocks. Our laboratory is unique in how it carries out basic research with an eye to applying the findings to humans.

If we used the in vivo luminescence measuring method, we would be able to continue to carry out extensive experiments while keeping mice alive. We feel that using this advantage would also make research on aging possible. Elderly people are often said to go to bed early and get up early. If we can use mice that show similar tendencies and find out why aging shortens the biological clock cycle, we may then be able to apply this knowledge to humans as well.

Our research on chrono-nutrition entitled “The Development of Next-Generation Meal and Exercise Menus, Based on Chrono-Nutrition and Exercise with Consideration for the Elderly” was selected as one of the Cross-ministerial Strategic Innovation Promotion Program (SIP). We study themes such as the types of breakfast menus that “reset” the biological clock, food ingredients that help increase cognitive functions and bone density, and exploration of the timing of ingesting such ingredients. In other words, it includes the development of a recipe that works for the circadian clock. Along these lines, I personally take note of the relationship between intestinal bacteria and biological clocks. A recent study found that when a person travels abroad, intestinal bacteria become disrupted, and bacteria that lead the body to increased levels of obesity increase. These findings may suggest the need to first consider intestinal health in order to keep our biological clocks healthy.

Biological clocks are a field that is open to a broad range of human applications, so I wish to continue conducting research with all due sincerity.

Interview and composition: Maki Yamamoto
In cooperation with: Waseda University Graduate School of Political Science J-School

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