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Biologic Clocks & Cycles, Explained!

Sleep is more than just an escape into oblivion during the night.

The daily light-dark cycle governs rhythmic changes in the behavior and/or physiology of pretty much all species on the planet [1]. These daily rhythms are not simply a response to the 24-hour changes that take place in the physical space due to the Earth turning on its axis, but instead arise from timekeeping systems within each organism [1]. 

There are circadian cycles (circadian arising from the Latin “circa diem” meaning “about a day” [1]), or rhythms, that regulate the sleep/wake cycle, as well as other cycles that are important for health and wellbeing, governing a huge variety of diverse systems.  

This article will explore several of these important elements of chronobiology and how they impact overall health and wellbeing. 

The Body’s Clocks 

There are various different types of biological clocks in the body, including circadian, ultradian, and infradian. These will be discussed in depth below, but suffice to say that they serve to control a vast array of physiological processes in the body and ensure that everything runs smoothly [2]. Biological clocks drive or alter our sleep patterns, alertness, mood, physical strength, blood pressure, as well as most other aspects of our physiology and behavior [3]. 

The Sleep/Wake Cycle

Neurotransmitters (chemicals in the brain and nervous system) including histamine, norepinephrine, and serotonin are released in the brainstem. The onset of sleep is governed by the interacting forces of the ‘sleep drive’, which steadily increases the longer we remain awake, as well as circadian fluctuations [4].   

In the anterior hypothalamus, sleep-promoting neurons release GABA and block the wakefulness-associated regions in the brainstem [5], a process that supports slow-wave sleep. During rapid eye movement (REM) sleep, regions of the brainstem that are typically dormant during wakefulness and slow wave sleep [4,6]. Ascending projections from cholinergic neurons in the brainstem stimulate the thalamus which increases the firing rate of neurons within the cortex. 

The timing of sleep is under control of the circadian pacemaker, which integrates input from photoreceptor cells in the retina [7], among other things.  

Circadian Rhythms 

Circadian rhythms, such as the sleep/wake cycle above, are governed by the genetically inherited brain clock network. The inherited period of circadian clocks is actually slightly greater than 24 hours in most people, but in some it is slightly less than 24 hours. These rhythms are the most widely studied in mammals, and are prevalent in virtually all aspects of biology including gene expression, protein modification, enzyme activity, metabolic and physiological processes, and behavior [8].  

Melatonin concentrations in the blood follow a prominent circadian pattern, with its production occurring almost exclusively at night. When light enters the eyes from the Sun, melatonin production by the pineal gland is blocked and wakefulness is triggered. In darkness, the pineal gland is stimulated to produce melatonin, that brings about tiredness. 

Exposure to light at an unusual time – such as when traveling rapidly across time zones or when working night shifts – causes compensatory changes in the suprachiasmatic nucleus (SCN)-pineal gland clock network that last several days. The integrity of the circadian time structure plays a key role in biologic and cognitive functioning – hence why ‘jet lag’ causes such acute brain draining effects [9,10].     

This so-called ‘phase misalignment’ due to a one-size-fits-all chronotype is associated with several negative effects and has been described as a public health concern. The impact of technology on circadian consistency is also a challenge, in particular the role of computers, tablets, and phones that emit blue light that may block melatonin production [11].   

Outside of the ‘master circadian clock’, there are other circadian rhythms in pretty much every organ and cell in the body, including the lungs, liver, pancreas, spleen, thymus, and skin to name a few. For instance, the Per3 gene appears to play a role in circadian timekeeping in central and peripheral clocks [12,13].  

What are Infradian Cycles?

In contrast with circadian cycles that have a frequency of one cycle every 24 hours, infradian (derived from the Latin “infra diem” meaning “less than a day”) rhythms have a frequency of less than one cycle every 24 hours.  

Some examples of infradian rhythms in mammals include migration, hibernation, and reproductive behavior [14,15]. In humans, research from the early 2000s showed that blood pressure has infradian characteristics, correlating with meteorological variables. Blood pressure when awake had a mainly circannual variation, whereas blood pressure when asleep exhibited a 3-month rhythm [16]. 

What are Ultradian Cycles?

A large number of biological clocks fall into the category of ultradian rhythms, cycles that occur across a broad time frame spanning seconds, minutes, and hours [17]. Ultradian and circadian clocks might share common elements at the molecular level.   

One of the first ultradian rhythms to be studied in humans was the REM-NREM sleep cycle which has a period of about 90 min and occurs 3 – 5 times within the average sleep episode [17].  

Other ultradian rhythms include the circulation of the blood supply/blood pressure [18], secretion of growth hormone [19], and liver function [20]. The liver in particular has been shown to have a 12-hour rhythm, with the expression of over 200 genes cycling at sunrise and sunset – two ‘rush hour’ periods [21].    

The existence of shorter ultradian cycles for protein and amino acid recycling might serve as an adaptation to acute environmental changes at low energy cost, while also resisting the accumulation of misfolded and therefore dysfunctional proteins [20].   

Interactions and Overlap Between the Timing Systems

Some physiological systems, such as cortisol release and the menstrual cycle, are controlled by more than one biological timing system. Cortisol release, for example, has both circadian and ultradian aspects, whereas the menstrual cycle has circadian and infradian components [15]. 

The menstrual cycle overlaps both timing systems in several ways. Women with ovulatory menstrual cycles have a circadian rhythm that is ‘superimposed’ on the menstrual-associated rhythm, and menstrual events in turn affect the circadian rhythm [22]. Research on women in the mid-follicular and mid-luteal phases of the menstrual cycle has demonstrated an interaction between circadian and menstrual processes in the regulation of rapid eye movement or REM sleep [23]. In addition, reproductive hormones not only regulate reproductive function during the menstrual cycle, they also influence sleep and circadian rhythm [24,25].  

The menstrual cycle also has infradian aspects too, given that it is a biological cycle with effects on physical and mental health that span a period longer than 24 hours. 

Elsewhere, sperm cells have shown an ultradian rhythm in variation, with a cycle every 2 hours, but have also shown two infradian rhythms of 12 months selected for physiological traits [26].  

Influence on Pathophysiological Conditions

Vasovagal syncope is a condition where a person faints following exposure to certain triggers, such as the sight of blood or during extreme emotional distress. This is caused by a sudden drop in heart rate and blood pressure, brought about by a failure of the body to adequately regulate blood pressure leading to insufficient delivery of blood to the brain [27,28]. 

Interestingly, vasovagal syncope has shown evidence of a circadian and infradian rhythm in young and middle-aged adults [29]. Frequency of episodes was higher in the morning and during the middle of the week, and a significant difference was found between weekdays and weekend days (around 76% compared with 25%).    

Conclusion

The body's clocks are myriad and complex, regulating practically every cellular process and making us extremely adaptable to our environment. 

The key, as always, is to understand how to make these clocks work for you and with you, rather than against you.  Get good rest at night. Understand your menstrual cycle and the changes that are ongoing both daily and minute-to- minute.  And if you have high blood pressure, there may be better times to take your medications due to natural spikes as well. This is why ambulatory blood pressure monitoring can be so helpful by the way! 

In short: Know your clocks and cycles, then leverage them, Tro Nation! 

References 

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[21]      M.E. Hughes, L. DiTacchio, K.R. Hayes, C. Vollmers, S. Pulivarthy, J.E. Baggs, S. Panda, J.B. Hogenesch, Harmonics of circadian gene transcription in mammals, PLoS Genet. 5 (2009) e1000442.https://doi.org/10.1371/journal.pgen.1000442

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[23]      A. Shechter, F. Varin, D.B. Boivin, Circadian Variation of Sleep During the Follicular and Luteal Phases of the Menstrual Cycle, Sleep. 33 (2010) 647–656.https://doi.org/10.1093/sleep/33.5.647

[24]      Y. Komada, Relationship of women’s reproductive health and menstrual problems with sleep and circadian rhythm, Sleep Biol. Rhythms. 18 (2020) 1–1.https://doi.org/10.1007/s41105-019-00247-8

[25]      S. Nowakowski, J. Meers, E. Heimbach, Sleep and Women’s Health, Sleep Med Res. 4 (2013) 1–22.https://doi.org/10.17241/smr.2013.4.1.1

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