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Chronobiol Med > Volume 6(2); 2024 > Article
Lee: Why Do Circadian Rhythms Exist?
Circadian rhythms have evolved as a result of adapting to the Earth’s consistent 24-hour rotation and its 23.5-degree tilt while orbiting the Sun. These environmental conditions create daily and seasonal cycles, necessitating life forms to adapt. From early microorganisms to complex vertebrates, all life on Earth has developed genes that govern circadian rhythms to prepare for day-night changes. For early microorganisms, sudden exposure to UV light during the day posed a threat, prompting the evolution of mechanisms to predict and prepare for these changes, resulting in circadian rhythms [1].
However, humanity first realized the existence of circadian rhythms in the 18th century when French scientist Jean Jacques d’Ortous de Mairan observed that mimosa plant leaves opened and closed in a 24-hour cycle, even in constant darkness [2]. This suggested an internal biological clock. In 1971, Konopka and Benzer [3] discovered a gene in fruit flies, called “period,” that influenced circadian rhythms. Later, Jeffrey C. Hall, Michael Rosbash, and Michael Young elucidated the mechanisms, discovering that the period gene and timeless gene work together to create a circadian rhythm matching the 24-hour day-night cycle [2]. Research on fruit flies revealed that the period gene’s expression starts during the day, producing PER protein in the cytoplasm. At night, PER moves into the nucleus, inhibiting the period gene’s activity and creating a 24-hour cycle [4]. The TIM protein, produced by the timeless gene, binds with the PER protein, enabling its entry into the nucleus. Consequently, the PER protein inside the nucleus can inhibit the operation of the period gene. Furthermore, a protein produced by another gene named doubletime, DBT, ensures that the PER protein does not accumulate in the cyCIMtoplasm and is instead degraded. Thanks to the DBT protein, the PER protein disappears in time, allowing the 24-hour circadian rhythm to proceed smoothly [5].
In mammals, the CLOCK:BMAL1 complex binds to Period and Cryptochrome genes, producing PER and CRY proteins. At night, these proteins inhibit CLOCK:BMAL1 activity, creating a feedback loop. This core loop, along with an auxiliary loop involving REV-ERBα and RORα genes, generates a stable 24-hour rhythm. Human circadian rhythms, slightly longer than 24 hours, adapt to environmental changes through morning light, which advances the rhythm daily. Circadian rhythms regulate almost all physiological functions, including sleep-wake cycles, body temperature, heart rate, blood pressure, and hormone levels. For example, cortisol peaks around 6 AM, while melatonin peaks at 3–4 AM and is suppressed by morning light. These rhythms influence unconscious actions and the timing of disease symptoms [6].
Light is the most potent regulator of circadian rhythms. Light entering the eyes signals the suprachiasmatic nucleus (SCN) in the brain, adjusting the circadian clock. The SCN processes light information, regulates melatonin secretion, and coordinates peripheral clocks through various pathways. While other factors like physical activity and meal times can influence peripheral clocks, light remains the strongest zeitgeber (time giver). A fixed 24-hour rhythm would make adapting to seasonal changes and time zone differences difficult. The phase response curve shows how light exposure at different times can advance or delay circadian rhythms. Exposure to morning light advances the rhythm, aligning it with the 24-hour cycle. Conversely, exposure to light late at night delays the rhythm, potentially causing insomnia. Maintaining a regular light exposure schedule, especially in the morning, is crucial for aligning circadian rhythms [7].
To optimize circadian rhythms, avoid bright lights late at night and use dim, yellowish lighting before bedtime. In the morning, expose yourself to bright light to advance the circadian rhythm. This practice helps maintain a 24-hour cycle, crucial for overall health and well-being. Circadian rhythms are essential for adapting to Earth’s environmental cycles. They influence nearly all physiological functions and behaviors, and maintaining a regular light exposure schedule is key to synchronizing these rhythms with the 24-hour day. Since many people are still unaware of the importance of circadian rhythms, it is the role of chronobiologists working in the medical field to raise awareness about the significance of maintaining healthy circadian rhythms for overall well-being.

NOTES

Funding Statement

This work was supported by grant number HI22C147200 from the Ministry of Health & Welfare.

REFERENCES

1. O’Neill JS, van Ooijen G, Dixon LE, Troein C, Corellou F, Bouget FY, et al. Circadian rhythms persist without transcription in a eukaryote. Nature 2011;469:554–558.
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2. Nobel Prize Outreach. Scientific background: discoveries of molecular mechanisms controlling the circadian rhythm [Internet] Available at: https://www.nobelprize.org/prizes/medicine/2017/advanced-information/. Accessed May 22, 2024.

3. Konopka RJ, Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A 1971;68:2112–2116.
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4. Allada R, White NE, So WV, Hall JC, Rosbash M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 1998;93:791–804.
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5. Bargiello TA, Young MW. Molecular genetics of a biological clock in Drosophila. Proc Natl Acad Sci U S A 1984;81:2142–2146.
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6. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK:BMAL1. PLoS Genet 2018;14:e1007156.
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7. Lee HJ. Circadian misalignment and bipolar disorder. Chronobiol Med 2019;1:132–136.
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