After finishing his overnight flight shift, a flight attendant boards a bus for his journey back home from the airport. The soft glow of dawn begins to emerge on the horizon. The bus driver has risen in the still-dark hours to start the day's work before sunrise. Among the passengers, many are absorbed in their smartphone screens. Perhaps without knowing it, by conforming to this modern, fast-paced way of life and work, they may be desynchronizing their internal clocks from the natural rhythms of day and night, leaving them susceptible to circadian rhythm disorders.

In a world that never seems to slow down, where the relentless tick-tock of the clock dictates our daily routine, there lies a different dimension of time waiting to be explored — a realm in which our body's inner clocks regulate the ebb and flow of our physiology. Welcome to the captivating realm of chronobiology, where time is not just a linear march forward but a complex, intricate oscillation, synchronized with the cycles of Earth’s movements. Have you ever wondered why some people are early birds, while others are night owls? Or why your energy and alertness fluctuate throughout the day? Chronobiology may have some answers.

What is Chronobiology?

Chronobiology is a fascinating field that explores biological rhythms, spanning from their molecular and cellular underpinnings to their influence on the behavior and physiology of entire organisms.

This article aims to describe how our internal clocks work to adapt to the cyclic changes we are exposed to. We will summarize the history of chronobiology before delving into the fascinating biological mechanisms that govern our circadian rhythms, and how they synchronize with the 24-hour day and night cycle. Finally, we will contemplate the potential implications that circadian rhythms have on our health and well-being.

So, prepare yourself, as in this article, we embark on a journey into the world of chronobiology, where time becomes more than just a measurement — it becomes a key to unraveling some of the intricate biological mechanisms affecting our health and physiology.

The Circadian Rhythm

In 1729, the astronomer Jean-Jacques d’Ortous de Mairan observed that the touch-me-not plant (Mimosa pudica), continued its “sleep” movements even in conditions of perpetual darkness. Carl Von Linné constructed in the 17th century a “floral clock” based on his knowledge of petal opening and closing times [1]. These early observations provided the first glimpses of an endogenous clock governing an organism’s behavior.

To underscore the concept of a 24-hour biological clock, Franz Halberg coined the term “circadian” in 1959. He derived it from the Latin words circa (about) and dies (day) to describe internally generated rhythms that persisted to oscillate even without external cues [1]. Throughout the 20th century, scientists reported circadian rhythms in different species, including bacteria [2], unicellular eukaryotes [3], birds [4], and humans [5], among others.

The hereditability of circadian rhythms was first proposed by Charles Darwin in 1880 [6] and later reported in bean plants by Erwin Bünning in the 1930s [7]. In the latter half of the 20th century, scientists unveiled the role of specific genes in regulating circadian rhythms across different species, thereby confirming the genetic control of the process and its heritability. Single gene mutations were found to disrupt the internal clock in fruit flies [8], hamsters [9], mice [10], and humans [11].

Genetics is not the sole explanation for circadian rhythm regulation. Other timekeeping mechanisms, such as redox oscillations in cells, have been shown to regulate the day and night cycle [12], going beyond the classic transcription-translation loop. Remarkably, scientists have succeeded in recreating a 24-hour cycle of cyanobacteria proteins in vitro, **even in the absence of gene transcription [13]. All these mechanisms, along with genes that govern circadian rhythms and external stimuli like light and temperature, collectively regulate our internal clock and oversee vital processes such as sleep or body temperature.

Thus far, we have explored the historical background of chronobiology and defined its concepts alongside that of circadian rhythm. In the subsequent sections, we will delve into the biological foundations of the circadian rhythm.

Clock synchronization: How does the circadian rhythm work?

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some mollusks, and it plays a pivotal role in processing visual information. The photosensitive area of the retina, the fovea, connects to the optic nerve and is responsible for transmitting visual data to the brain. Photoreceptors, which are the light-sensitive cells of the retina, include rods and cones. These photoreceptors are connected to bipolar cells, which, in turn, connect to specialized neurons known as retinal ganglion cells [14]. A very small subset of retinal ganglion cells, known as the intrinsically photosensitive retinal ganglion cells (ipRGC), serve as photoreceptors by expressing the photosensitive protein melanopsin [15].

Together with rods and cones, ipRGC and melanopsin contribute to the intricate process of photoentrainment (the synchronization of the internal circadian clock with the natural light and dark cycle). However, the precise roles of these different photoreceptors in entrainment are still not fully understood, particularly due to the existence of various types of ipRGC, each linked to distinct areas of the brain [15]. The photoreceptor network of the retina is connected to the suprachiasmatic nucleus (SCN), a cluster of neurons situated in the hypothalamus. When photoreceptors detect light, they activate the SCN. Subsequently, the SCN initiates a sequence of physiological responses that establish daily rhythms, including the suppression of melatonin production by the pineal gland. Therefore, the SCN functions as a pacemaker, synchronizing the external cues, referred to as zeitgebers, with the central internal clock. In the context of the circadian rhythm, the primary zeitgeber is daylight. The SCN maintains synchrony with peripheral circadian clocks through neuronal and humoral stimulation. These peripheral clocks are influenced by other zeitgebers such as temperature, exercise, social interaction, or feeding [16]. For instance, meal timing induces notable changes in the lipidome and post-translational modifications of the proteome in the mouse liver [17].

On a molecular level, two crucial genes, the Circadian Locomotor Output Cycles Kaput (CLOCK) and the Brain and Muscle ARNT-Like 1 (BMAL1), encode for a heterodimeric transcription factor known as CLOCK/BMAL1. This transcription factor activates genes containing E-box promoters, which encompass core clock genes such as Period (PER1 and PER2) and Cryptochrome (CRY1 and CRY2) genes, along with various clock-controlled genes linking the circadian oscillator to physiological and metabolic processes. Once formed, PER/CRY protein complexes migrate to the nucleus, where they inhibit the transcription of E-box genes, including their own, thereby constituting an autoregulatory negative feedback loop [18,19].

De-synchronizing our clocks

Evolution takes place on a planet that rotates around its axis while orbiting around the Sun, resulting in the day and night cycle and the changing seasons. Thus, the majority of life on Earth, including our ancestors, has evolved in a cyclically changing environment. Consequently, species have developed internal circadian systems that enable them to anticipate and adapt to these changes effectively. These internal clocks are finely synchronized not only with the natural day and night cycle but also with the changing seasons in the case of plants and with tidal cycles in the case of marine fauna. But what happens when these rhythms are disrupted?

Some of the cycles we are exposed to are rapidly changing. Climate change is modifying rainfall patterns, temperature, and the timing of seasons. On the other hand, the contemporary way of life is continually altering the patterns of day and night. Artificial lighting, screens, and shift work are prime examples of interferences with the natural light and dark cycle. Such disruptions can lead to a range of disorders and diseases, including sleep disorders, cancer, and obesity.

Essential cellular processes, such as cell cycle progression, cytokine release, hormone secretion, and immune regulation, are orchestrated by an internal clock influenced by the day and night cycle [20,21]. As a consequence, misalignments between the 24-hour cycle and circadian oscillators lead to the alteration of fundamental biological and physiological processes. For instance, human subjects may experience imbalances in glucose homeostasis, insulin action, and appetite control when maintained in circadian misalignment conditions [22]. In animals, the desynchronization between internal clocks and external cues induced disorders like diet-induced obesity [23] or a light-induced pro-inflammatory state [24], among others.

An increasing body of research has shed light on the link between circadian rhythm desynchronization and the onset of diseases in humans. For instance, abnormal expression of the clock gene PER2 has been associated with the development of oral squamous cell carcinoma and other types of tumors [25,26]. Other diseases related to circadian rhythm alterations include obesity [27], diabetes [28], cardiovascular disease [29], and sleep disorders [30]. Neurodegenerative diseases like Alzheimer’s disease, dementia, and Parkinson’s disease have also been associated with circadian rhythm alterations, though additional studies are needed to establish causality [31].

The impact of circadian rhythm disturbances on psychological aspects is another interesting area of research, with growing evidence highlighting the pivotal role the day and night cycle plays in mental health. Exposure to irregular light cycles in rats induced changes in the pattern of the neurotransmitters dopamine and somatostatin in specific areas of the brain, resulting in depression-like symptoms and impaired learning [32]. In addition, malfunction of the circadian rhythms or lack of entrainment causes sleep disorders known as circadian rhythm sleep-wake disorders (CRSWD). While the exact causes of these sleep disorders are not completely understood, genetic predisposition may be a contributing factor. Additionally, environmental factors such as limited daylight in the morning and increased light exposure at night are believed to contribute to the development of CRSWD. Behavioral factors, including night-shift work, excessive caffeine consumption, poor sleep habits, reduced amounts of morning light, or heavy exposure to bright lights or electronic screens at night, can also lead to disturbances in sleep patterns. These types of sleep disorders are often therapeutically addressed with sleep education, time therapy, light therapy, melatonin, and hypnotic drug therapy [33].

Chronobiology in Health Optimization Medicine and Practice (HOMe/HOPe)

Are you a practitioner interested in learning more about chronobiology and how to use it in your clinical practice? One of the 7 pillars of the Essential Certification of HOMe/HOPe is Chronobiology. In this module, practitioners will learn how to detect and correct chronobiological imbalances using lifestyle measures as well as lab testing and supplementation. This also includes a deep dive into circadian physiology as well to further practitioners’ understanding of the intricate chronological systems.

Check out the Chronobiology module in the HOMe/HOPe Essential Course here.

Conclusion: Listen to your inner clock

The Industrial Revolution and the invention of the light bulb, which provides illumination for our homes at night, unquestionably marked incredible progress for humanity. More recently, computers and smartphones have granted us instantaneous access to vast amounts of information. However, every advancement comes with its downside: we are now compelled to disrupt the entrainment between our circadian rhythms and the natural day and night cycle if we wish to adapt to modern lifestyles.

The wealth of knowledge generated by researchers over the last few decades allows us to grasp the importance of our biological clocks and the impact the light and dark cycle has on our health and well-being. We now understand that night workers and shift workers face a higher risk of circadian rhythm-related disorders, including conditions such as cancer or diabetes. The indiscriminate use of computer screens and smartphones can also contribute to these disorders.

A profound comprehension of the value of healthy sleeping habits and smarter working schedules, along with rational screen usage in the evening, can indeed alleviate circadian rhythm alterations [34]. We presently live in a world that appears to whirl at an ever-increasing pace, adorned with millions of gleaming night lights and a surfeit of information. Rather than attempting to keep up with the relentless rush that never seems to halt, we should strive to live in harmony with our inner clock.

Written by Ferran Riaño-Canalias, PhD

References

1. Chandrashekaran MK. Biological rhythms research: A personal account. J Biosci. 1998;23(5):545-555. doi:10.1007/BF02709165

2. Mitsui A, Kumazawa S, Takahashi A, Ikemoto H, Cao S, Arai T. Strategy by which nitrogen-fixing unicellular cyanobacteria grow photoautotrophically. Nature. 1986;323(6090):720-722. doi:10.1038/323720a0

3. Sweeney BM, Hastings JW. Characteristics of the diurnal rhythm of luminescence in Gonyaulax polyedra. J Cell Comp Physiol. 1957;49(1):115-128. doi:10.1002/jcp.1030490107

4. Kramer. G. Experiments on Bird Orientation *. Ibis. 1952;94(2):265-285. doi:10.1111/j.1474-919X.1952.tb01817.x

5. Von Aschoff J, Wever R. Spontanperiodik des Menschen bei Ausschluß aller Zeitgeber. Naturwissenschaften. 1962;49(15):337-342. doi:10.1007/BF01185109

6. Darwin C. The Power of Movement in Plants. Cambridge University Press; 2009. doi:10.1017/CBO9780511693670

7. Moore-Ede MC. The Clocks That Time Us : Physiology of the Circadian Timing System. Cambridge, Mass. : Harvard University Press; 1982. Accessed October 18, 2023. http://archive.org/details/clocksthattimeus0000moor

8. Konopka RJ, Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971;68(9):2112-2116. doi:10.1073/pnas.68.9.2112

9. Ralph MR, Menaker M. A mutation of the circadian system in golden hamsters. Science. 1988;241(4870):1225-1227. doi:10.1126/science.3413487

10. Vitaterna MH, King DP, Chang AM, et al. Mutagenesis and Mapping of a Mouse Gene, Clock, Essential for Circadian Behavior. Science. 1994;264(5159):719-725. doi:10.1126/science.8171325

11. Jones CR, Campbell SS, Zone SE, et al. Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nat Med. 1999;5(9):1062-1065. doi:10.1038/12502

12. Ray S, Reddy AB. Cross-talk between circadian clocks, sleep-wake cycles, and metabolic networks: Dispelling the darkness. BioEssays. 2016;38(4):394-405. doi:10.1002/bies.201500056

13. Nakajima M, Imai K, Ito H, et al. Reconstitution of Circadian Oscillation of Cyanobacterial KaiC Phosphorylation in Vitro. Science. 2005;308(5720):414-415. doi:10.1126/science.1108451

14. Baden T, Euler T, Berens P. Understanding the retinal basis of vision across species. Nat Rev Neurosci. 2020;21(1):5-20. doi:10.1038/s41583-019-0242-1

15. Lucas RJ, Lall GS, Allen AE, Brown TM. How rod, cone, and melanopsin photoreceptors come together to enlighten the mammalian circadian clock. In: Progress in Brain Research. Vol 199. Elsevier; 2012:1-18. doi:10.1016/B978-0-444-59427-3.00001-0

16. McKenna H, van der Horst GTJ, Reiss I, Martin D. Clinical chronobiology: a timely consideration in critical care medicine. Crit Care. 2018;22(1):124. doi:10.1186/s13054-018-2041-x

17. Huang R, Chen J, Zhou M, et al. Multi-omics profiling reveals rhythmic liver function shaped by meal timing. Nat Commun. 2023;14(1):6086. doi:10.1038/s41467-023-41759-9

18. Mohawk JA, Green CB, Takahashi JS. Central and Peripheral Circadian Clocks in Mammals. Annu Rev Neurosci. 2012;35(1):445-462. doi:10.1146/annurev-neuro-060909-153128

19. Xie Y, Tang Q, Chen G, et al. New Insights Into the Circadian Rhythm and Its Related Diseases. Front Physiol. 2019;10. Accessed October 19, 2023. https://www.frontiersin.org/articles/10.3389/fphys.2019.00682

20. Panda S, Hogenesch JB, Kay SA. Circadian rhythms from flies to human. Nature. 2002;417(6886):329-335. doi:10.1038/417329a

21. Bass J, Takahashi JS. Circadian Integration of Metabolism and Energetics. Science. 2010;330(6009):1349-1354. doi:10.1126/science.1195027

22. McHill AW, Melanson EL, Higgins J, et al. Impact of circadian misalignment on energy metabolism during simulated nightshift work. Proc Natl Acad Sci. 2014;111(48):17302-17307. doi:10.1073/pnas.1412021111

23. Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW. Circadian Timing of Food Intake Contributes to Weight Gain. Obesity. 2009;17(11):2100-2102. doi:10.1038/oby.2009.264

24. Lucassen EA, Coomans CP, van Putten M, et al. Environmental 24-hr Cycles Are Essential for Health. Curr Biol. 2016;26(14):1843-1853. doi:10.1016/j.cub.2016.05.038

25. Xiong H, Yang Y, Yang K, Zhao D, Tang H, Ran X. Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. Int J Oncol. 2018;52(1):279-287. doi:10.3892/ijo.2017.4180

26. Savvidis C, Koutsilieris M. Circadian Rhythm Disruption in Cancer Biology. Mol Med. 2012;18(9):1249-1260. doi:10.2119/molmed.2012.00077

27. Antunes LC, Levandovski R, Dantas G, Caumo W, Hidalgo MP. Obesity and shift work: chronobiological aspects. Nutr Res Rev. 2010;23(1):155-168. doi:10.1017/S0954422410000016

28. Pan A, Schernhammer ES, Sun Q, Hu FB. Rotating Night Shift Work and Risk of Type 2 Diabetes: Two Prospective Cohort Studies in Women. PLOS Med. 2011;8(12):e1001141. doi:10.1371/journal.pmed.1001141

29. Angelousi A, Kassi E, Nasiri-Ansari N, Weickert MO, Randeva H, Kaltsas G. Clock genes alterations and endocrine disorders. Eur J Clin Invest. 2018;48(6):e12927. doi:10.1111/eci.12927

30. Logan RW, McClung CA. Rhythms of life: circadian disruption and brain disorders across the lifespan. Nat Rev Neurosci. 2019;20(1):49-65. doi:10.1038/s41583-018-0088-y

31. Leng Y, Musiek ES, Hu K, Cappuccio FP, Yaffe K. Association between circadian rhythms and neurodegenerative diseases. Lancet Neurol. 2019;18(3):307-318. doi:10.1016/S1474-4422(18)30461-7

32. Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC. Neurotransmitter Switching in the Adult Brain Regulates Behavior. Science. 2013;340(6131):449-453. doi:10.1126/science.1234152

33. Sun SY, Chen GH. Treatment of Circadian Rhythm Sleep–Wake Disorders. Curr Neuropharmacol. 2022;20(6):1022-1034.

34. Eisenstein M. Chronobiology: Stepping out of time. Nature. 2013;497(7450):S10-S12. doi:10.1038/497S10a