Ticking time bomb? High time for chronobiological research

Abstract

The 2017 Nobel prize for elucidating the mechanisms of chronobiology highlights the urgent need to better understand our internal clockwork and its effects on health and disease.

The field of chronobiology was thrust into the spotlight with the 2017 Nobel Prize in Physiology or Medicine awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for elucidating the genetic makeup and mechanism of our internal 24‐h clock. In addition to recognizing their groundbreaking work, the prize should also serve as a call for molecular and epidemiological research into how our internal 24‐h clock influences health and disease.

Indeed, neglecting our internal 24‐h timing system, which coordinates countless fundamental physiological processes, can exacerbate ill‐health conditions such as psychiatric disorders, obesity, diabetes, cardiovascular disease, and possibly even cancer 1, 2, 3. Unfortunately, most humans pay little attention to their internal clock and daily light exposure (a key cue for setting and regulating the clock) and too often push their bodies beyond their clocks’ capabilities 1. Understanding how this may affect health and disease, how certain lifestyles may allow us to work in tune with environmental time (i.e., natural daylight), and how to diffuse a potential ticking time bomb of long‐term health risks is therefore a highly important research endeavor. Concerted and complementary molecular and epidemiological research in chronobiology can assist such ventures 4, 5.

From an evolutionary perspective, it is vital that organisms are able to adapt to the varying demands of the 24‐hour day, including fluctuations in light–darkness, temperature, food availability, and predation. Unsurprisingly, a striking evolutionary legacy of our internal timing system is its ability for constant yet gradual realignment to changing light–dark cycles over days and seasons that is consciously imperceptible and a trait shared by many species. This evolutionary clockwork is referred to as the “circadian” system, from the Latin circa (approximately) and dies (day).

Within every cell in the body, “clock” genes work on approximately 24‐h expression loops to control the 24‐h periodicity of physiology and behavior 6. The clock in each cell is coordinated by a “master” pacemaker in the anterior hypothalamus of the brain called the suprachiasmatic nuclei (SCN), which is predominantly sensitive to light–dark changes transmitted inter alia through newly discovered light receptors (melanopsin‐expressing retinal ganglion cells) in the eyes 7. The release of hormones, cell growth and repair processes, metabolism, detoxification, body temperature, blood pressure, sleep, and even immune system function represent but a few of the biological processes that are regulated by the circadian system. Thousands of genes in every cell in the body need to be turned on and off at appropriate times and in correct sequence to allow this critical, temporal organization of physiology; thus ensuring circadian rhythm alignment internally and in respect of environmental time (externally). Two well‐known examples of circadian timing are cortisol release (a stress hormone from the adrenal gland) in concert with waking up in the morning and first light exposure and melatonin release (the “Dracula” hormone from the pineal gland) coordinated with evening dim light and the onset of sleepiness.

While the light–dark cycle is considered the key evolutionary zeitgeber (from German, “time cue”), other zeitgebers that can influence circadian biology include the timing of food intake, physical activity, and social contact. Our internal clockwork evolved to allow circadian rhythm alignment to achieve peak performances during the day (e.g., energy allocation, increased body temperature) and to prepare for sleep and sleep‐associated processes during the nighttime (e.g., growth and repair, memory consolidation, information processing). The entrainment of physiological rhythms to light–dark rhythms and other zeitgeber exposures is critical for robust, aligned circadian rhythms, which are important for health, timing of peak performance levels, or when medical treatments will produce strongest effects. Thus, brief disruption or misalignment of circadian processes can perceptibly impact general health, and physical and cognitive performance. Flying to a new time zone and adapting to a sudden and significant change in environmental light and social times results in the lethargy, nausea, bowel problems, and decreased performance levels which together are commonly known as jet lag—just one example of immediate or short‐term effects of the biological clock running counter to the environmental or social clock.

Long‐term consequences of circadian disruption may include psychiatric disorders, obesity, diabetes, cardiac disease, and cancers 1, 2, 3. It is now widely accepted in research that modern lifestyles cause insufficient or inappropriate light exposure on our circadian timing system, which likely contributes to the current epidemic of sleep deficiency in developed societies 8. Indeed, the timing of most zeitgebers is determined by work and school schedules in modern society. Inappropriate light can stem from shift work, travel across time zones, weekday–weekend timing differences, low‐intensity indoor lighting compared to the much more intense sunlight, daylight savings time change, electronic device light exposure at night, or light pollution from street lights and house lights. Schoolchildren getting up earlier on schooldays and using light emitting devices such as televisions, laptops, and smartphones at nighttime can be expected to be at increased risk. In adults, the timing differences in light exposure, social contact, and sleep between a 5‐day work week and a 2‐day weekend may result in only 1 or 2 days per week when circadian rhythms are physiologically aligned and 5–6 days of misalignment. Over 30 years of work, this could equate to approximately 26 years of misaligned internal time. Are we sure 26 years of mistimed and/or insufficient gene expression, sleep, hormone secretion, immune system function, and metabolism will not increase the risk of developing a disease or aggravating preexisting pathologies?

In fact, the global burden of diseases that might be associated with disturbed chronobiology is increasing. Similarly, there may be a link between climbing cancer rates and increasing man‐made light 9. Moreover, if mice are forced to experience a rapidly changing light–dark cycle, similar to the changes experienced by human shift workers, the mice develop multiple pathologies and show reduced life expectancy 1. Such data strongly suggest that circadian disruption can promote or even cause disease and poor health. However, without further research we cannot put numbers on how much circadian disruption or living against our clocks both at work and at play is associated with disease 10.

There is an urgent need to establish long‐term sleep cohort studies alongside circadian phenotyping and other circadian measures. For example, cohort studies of pre‐teenage children have measured various health parameters, but none of the longitudinal studies have adequately looked at sleep or circadian measures over prolonged periods. Such data would be critical in assessing the impact of sleep and circadian rhythm disruption on educational outcomes, health, and vulnerability to disease. In addition, such studies in adults would be able to define the impact of societal factors on sleep disruption, such as shift work, jet lag, and work‐related stress. It would allow us to understand, and possibly prevent, the development of various diseases that may result from living against one's clock. Ultimately, epidemiological studies will be imperative to judge whether what we observe in subcellular biochemistry, cells, organs, and non‐human organisms is relevant both for humans and public health 5. Clearly, there is a lack of awareness of the potential dangers of abusing one's internal clock. Equally clearly, this state of affairs should be addressed by concerted molecular and epidemiological research efforts.

Conflict of interest

The authors declare that they have no conflict of interest.