Tick-tock, tick-tock… What’s the time in your body?

The impact of chronodisruption

Biological rhythms represent a key means to ensure physiological order and avoid pathological disorders. [1]

Nowadays, our society is increasingly leading a 24/7 lifestyle. People tend to spend more and more time indoors, rarely exposed to solar light and other environmental stimulations. In addition, irregular sleeping behaviors, intense shift-works, misalignment of social and biological times are all factors that can cause an impairment of the circadian system.

Also denoted as “chronodisruption”, this phenomenon refers to a significant disorder of the internal temporal order of the circadian rhythm, as a major consequence of a living context characterized by weak, absent or contradictory environmental cues. [2] This circadian asynchrony represents a real environmental challenge for our biological adaptation to the natural cycle of light and darkness.

A 24-hour society

Our daily life is regulated by different kinds of “clocks”.

To name some examples, there is a solar clock, which is guided by light and warmer temperatures during the day as opposed to the night; a social clock, imposed by the schedule of our jobs and daily routines; and a biological clock, which is usually perceived more intensely during jet-lag, a shift work, or after a sleepless night. Even when concealed from the first two clocks, the biological clock is characterized by an endogenous free-running period that lasts approximately 24 hours. In real life, however, external periodic inputs – known as the German word “Zeitgebers”, (“time-givers”) – do exist and biological clocks are synchronized with the 24 hours of the solar clock, through a process called entrainment. [3]

The circadian clock

Daily rhythms are an important feature of life and a wide variety of processes follows a 24-hour (circadian) cycle.

Circadian rhythms are genetically controlled by our “body clocks”, located in nearly every cell, that set up an internal timing of approximately 24 hours, even in absence of external cues. [4] These molecular clocks are then organized into an endogenous hierarchical timekeeping system and regulated by the so-called “master” clock: the suprachiasmatic nucleus (SCN). Located in the anterior hypothalamus, the SCN is composed of about 20,000 neurons that create a highly coherent circadian network. [5] Only this master clock receives light inputs from the retina, synchronizing the internal system to the external solar day. Other biological clocks are found in peripheral tissues (for example in the liver, kidneys, heart, lungs) and adapt to adjustments from the SCN via circulating hormones and other metabolic cues, as well as systemic changes, such as body temperature. [4]

In line with this, new technologies have been developed in order to simultaneously monitor the expression pattern of “clock genes”, located in multiple sites. For example, Hamada and colleagues (2016) [6] were able to track at the same time six different body regions (including olfactory bulbs, ears, skin, and parts of the brain) in moving and fully conscious mice, placed in dark cages. They successfully managed to identify  the 3d positions of the target areas, by attaching fluorescent scintillators to their bodies and heads, which emitted a light signal  when clock genes turned on.

Mechanisms of sleep regulation

As mentioned earlier, the brain’s circadian clock is principally involved in the regulation of daily physiological activities and behavioral patterns, from feeding to hormone production, to cell regeneration and to core body temperature balance. Above all, the circadian system coordinates sleep.

In the last few decades, sleep research has been dominated by the “two-process model” of sleep regulation. Originally proposed by Borbély (1982) [7] and Daan et al. (1984) [8], the model suggests an interaction between a homeostatic sleep-dependent process (process S) and a sleep independent circadian process (process C) in the control of salient aspects of the sleep-wake cycle. In other words, the circadian clock centred in the hypothalamus plays an important role regulating the timing of sleep, according to the light-dark cycle over the 24-hour period, but independently from the preceding amount of sleep or wakefulness. However, the circadian rhythm alone appears to be insufficient to cause and control sleep: an additional sleep-wake homeostatic process works as an intuitive system reminding the body the need to sleep after a certain time. Moreover, additional external factors (e.g. stress, exercise, meal times, daily schedules) can have a more or less direct impact on the individual’s sleep-wake cycle. [9]

The role of melatonin

Human beings are naturally a diurnal species, as reflected by our circadian rhythms too.

An essential hormone affected by the circadian clock, at least regarding sleep, is melatonin, produced by the pineal gland and responsible for feelings of drowsiness and lower levels of body temperature. Its rhythmic synthesis is influenced by dark environments, with melatonin serum levels starting to rise after nightfall (around 8-9 PM), peaking during the middle of the night (around 2-4 AM) and stopping in the morning (around 7-9 AM). [10] In parallel, body temperatures usually decline at night, reaching a minimum around 4-5 AM.

That is, if we sleep at the “right” moment of the circadian cycle, our lowest body temperature and maximum melatonin concentration should occur towards the end of the sleeping period.

Shift-work: an example of circadian misalignment

A representative reflection of a 24-hour society is shift work. Usually the term describes a wide range of working hours arrangements; in this context, it expressly indicates all working times that differ from the traditional diurnal ones, comprising early starts, compressed work weeks and night jobs. [11] “According to recent American and European surveys, between 15 and 30% of adult workers are engaged in some type of shift work, with 19% of the European population reportedly working at least 2 hours between 22:00 and 05:00” (Boivin and Boudreau, 2014). [12]

Although the increase of shift-work has introduced some benefits in the modern society, such as greater flexibility in work schedules, possibility to provide goods and services throughout all day and night, and more employment opportunities, the negative effects on health and productivity are recently being more appreciated and investigated. [13] The main disadvantages of shift-work can be summarized into three broad categories, including:

  • Cognitive-behavioural effects: when sleep reduction accumulates over consecutive days, shift workers typically suffer from fatigue and sleepiness. This generally leads to poorer alertness, lower vigilance and impaired performance levels. [12]
  • Safety effects: sleep debt resulting from shift work has been associated with an increased amount of accidents and injuries. According to recent findings, workers sleeping less than 6 hours per day have an 86% more chance of accidents than those sleeping 7 to 8 hours per day. [14] The risk becomes particularly dangerous when working with motor vehicles or in emergency-medical teams.
  • Health effects: in addition, when compared to day workers, shift workers show higher risks of on-going health problems such as cardiovascular disorders, obesity, gastro-intestinal diseases, diabetes, and some forms of cancer, but also psychological problems, as mood disorders. All these conditions may in part explain the high rates of absenteeism and long-term inabilities often reported in shift workers. [12]

To sum up…

Disruption of circadian control through extrinsic factors – such as shift work, jet lag – and intrinsic factors – such as circadian disorders – has wide spread effects on several aspects of neural and neuroendocrine functions which, in turn, negatively affect one’s personal well-being. [15] As we have seen, misalignment of the wake-sleep cycle leads not only to sleep disturbances, but also to many other problematic consequences. That is why biological timing appears to be a relevant issue also when thinking about the health and the productivity of a nation.

Many countermeasures have been proposed to mitigate the symptoms related to circadian misalignment. In the context of shift-work, increasing light intensity in the workplace and adjust its wavelength toward the blue end of the spectrum (and so making it more similar to the natural daylight) may promote circadian adaptation to atypical work times and could help workers sleep during the day. Strategic napping of 20-30 minutes and melatonin intake have been also shown to be simple but effective measures for improving night performance. [12] Besides, a number of software is springing up aiming at improving sleep after late night computer activities. “F.lux”, for instance, works by dynamically warming the colours on the screen, thus imitating the light present in the room during nighttime (for more information, check justgetflux.com).  

Nevertheless, tolerance to shift-works still represents a complex and multifaceted problem. Pros and cons of countermeasures should be carefully weighted, taking into account their specific risks too. For instance, it has been suggested that light exposure during the night could inhibit the circulating level of melatonin and increase the risk of cancer. [11]

Further research on a multidimensional level is still needed to clarify the specific mechanisms that link misalignment to disease development. Another issue to address is how to improve circadian alignment for managing chronic illness, keeping in mind that each intervention measure should be considered and adapted to each individual work schedule and environment. [16]

References

  1. Erren, T.C., & Reiter, R.J. (2009). Defining chronodisruption. Journal of Pineal Research 46(3), 245-247. DOI: 10.1111/j.1600-079X.2009.00665.x
  2. Martinez-Nicolas, A., Madrid, J.A., & Rol, M.A. (2014). Day–night contrast as source of health for the human circadian system. Chronobiology International 31(3), 382-393.  DOI: 10.3109/07420528.2013.861845
  3. Roenneberg, T., Wirz-Justice, A., & Merrow, M. (2003). Life between Clocks: Daily Temporal Patterns of Human Chronotypes. Journal of Biological Rhythms 18(1), 80-90. DOI: 10.1177/0748730402239679
  4. Partch, C.L., Green, C.B., & Takahashi, J.S. (2014). Molecular architecture of the mammalian circadian clock. Trends in Cell Biology 24(2), 90-99. DOI: 10.1016/j.tcb.2013.07.002
  5. Evans, J.A., & Gorman, M.R. (2016). In synch but not in step: Circadian clock circuits regulating plasticity in daily rhythms. Neuroscience 320, 259-280. DOI: 10.1016/j.neuroscience.2016.01.072
  6. Hamada, T., Sutherland, K., Ishikawa, M., Miyamoto, N., Honma, S., Shirato, H., & Honma, K. (2016). In vivo imaging of clock gene expression in multiple tissues of freely moving mice. Nature Communications, 7. DOI:10.1038/ncomms11705
  7. Borbély, A.A. (1982). A two-process model of sleep regulation. Human Neurobiology 1(3), 195-204
  8. Daan, S., Beersma, D.G., & Borbély, A.A. (1984). Timing of human sleep: recovery process gated by a circadian pacemaker. American Journal of Physiology 246(2 Pt 2), R161–R183
  9. Borbély, A.A, Daan, S., Wirz-Justice, A., & Deboer, T. (2016). The two-process model of sleep regulation: a reappraisal. Journal of Sleep Research 25(2), 131-143. DOI: 10.1111/jsr.12371
  10. McGrane, I.R., Leung, J.G., St Louis, E.K., & Boeve, B.F. (2015). Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Medicine 16(1), 19-26. DOI: 10.1016/j.sleep.2014.09.011
  11. Knutsson, A. (2004). Methodological Aspects of Shift-Work Research. Chronobiology International 21(6), 1037-1047. DOI: 10.1081/CBI-200038525
  12. Boivin, D.B., & Boudreau, P. (2014). Impacts of shift work on sleep and circadian rhythms. Pathologie Biologie 62(5), 292-301
  13. Rajaratnam, S.M.W., & Arendt, J. (2001). Health in a 24-h society. The Lancet 358(9286), 999-1005
  14. Lombardi, D.A., Wirtz, A., Willetts, J.L., & Folkard, S. (2012). Independent effects of sleep duration and body mass index on the risk of a work-related injury: evidence from the US National Health Interview Survey (2004–2010). Chronobiology International 29(5), 556–564. DOI: 10.3109/07420528.2012.675253
  15. Wulff, K., Gatti, S., Wettstein, J.G., & Foster, R.G. (2010). Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nature Reviews Neuroscience 11(8), 589-599. DOI: 10.1038/nrn2868
  16. Baron, K.G., & Reid, K.J. (2014). Circadian misalignment and health. International Review of Psychiatry 26(2), 139-154. DOI: 10.3109/09540261.2014.911149

Image credits

Wikimedia Commons, Pixabay, Creative Commons, Flickr

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