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Circadian rhythm as a therapeutic target

Abstract

The circadian clock evolved in diverse organisms to integrate external environmental changes and internal physiology. The clock endows the host with temporal precision and robust adaptation to the surrounding environment. When circadian rhythms are perturbed or misaligned, as a result of jet lag, shiftwork or other lifestyle factors, adverse health consequences arise, and the risks of diseases such as cancer, cardiovascular diseases or metabolic disorders increase. Although the negative impact of circadian rhythm disruption is now well established, it remains underappreciated how to take advantage of biological timing, or correct it, for health benefits. In this Review, we provide an updated account of the circadian system and highlight several key disease areas with altered circadian signalling. We discuss environmental and lifestyle modifications of circadian rhythm and clock-based therapeutic strategies, including chronotherapy, in which dosing time is deliberately optimized for maximum therapeutic index, and pharmacological agents that target core clock components and proximal regulators. Promising progress in research, disease models and clinical applications should encourage a concerted effort towards a new era of circadian medicine.

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Fig. 1: Hierarchical organization of the mammalian clock system.
Fig. 2: The cell-autonomous core components of the circadian oscillator govern the ~24-hour cycle of gene expression.
Fig. 3: Melatonin and orexin signalling in circadian rhythm.
Fig. 4: Pharmacological interventions for insomnia and jet lag.

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Acknowledgements

This work was in part supported by US National Institute of Health grants R01HL154720, R01DK122796, R01DK109574, R01HL133900 and Department of Defense Grant W81XWH2110032 to H.K.E., an American Thoracic Society unrestricted grant, American Heart Association grant 19CDA34660279, American Lung Association grant CA-622265, the Center for Clinical and Translational Sciences pilot project award 1UL1TR003167–01 and a Parker B. Francis Fellowship to X.Y., and National Natural Science Foundation of China grants 81201448 and 81972312 and Natural Science Foundation of Hunan Province grant 2018JJ3736 to W.R. The authors thank S.-H. Yoo and Z. Chen for their help with the initial draft of the manuscript. The authors acknowledge Y. Wang and K. Wallen for assisting with manuscript editing.

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W.R. And X.Y. contributed equally and were involved in all aspects of this article. H.K.E. contributed substantially to discussion of the content and reviewed and edited the manuscript before submission.

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Correspondence to Holger K. Eltzschig.

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Glossary

Zeitgebers

A German word (meaning ‘time giver’), from Zeit (meaning ‘time’) and Geber (meaning ‘giver’). It refers to any external or intracellular cues that can reset or entrain an organism’s biological rhythms to the 24-hour day–night cycle of Earth.

Phase advance

A phase shift in the circadian rhythm whereby the bedtime and wake-up time will move earlier in the day.

Non-rapid-eye-movement sleep

Also known as quiescent sleep, with little or no eye movement, rare dreaming and less muscle paralysation than in rapid eye movement sleep.

Rapid eye movement sleep

Also known as paradoxical sleep, a unique phase of sleep in mammals and birds characterized by rapid eye movement, low muscle tone throughout the body and vivid dreaming sometimes.

Phase dissociation

In the context of this Review, the dissociation of intrinsic circadian rhythm and the environmental light–dark cycle, as in jet lag and sleep disorders.

Delayed sleep phase syndrome

A circadian sleep disorder in which a person’s sleep is delayed by 2 hours or more beyond what is considered a conventional bedtime, thus causing difficulty in waking up in the morning.

Ischaemic preconditioning

An experimental technique (usually via repeated short episodes of ischaemia via coronary artery occlusion) to increase tolerance to the loss of blood supply, and thus oxygen, if there is a subsequent prolonged insult.

Circadian wheel-running rhythms

When rodents have free access to a running wheel, voluntary use of this wheel is active during the night and inactive during the day to generate a specific circadian rhythm, which serves as a particularly reliable and convenient measure of the output of the master circadian clock.

Phase delay

A phase shift in the circadian rhythm whereby the bedtime and wake-up time will move later in the day.

Lipopolysaccharide challenge

An experimental technique to elicit inflammation by administering lipopolysaccharide via intraperitoneal injection to mice.

Caecal ligation and puncture

A commonly used preclinical rodent model to study sepsis via ligation and perforation of the caecum, resulting in polymicrobial infection and systemic inflammation.

Zeitgeber time

A standardized 24-hour notation for the phase in an entrained circadian cycle with reference to environmental regularities or zeitgebers.

Chronobiotic

An agent that is able to influence, directly or indirectly, the phase and/or the period of the body clock.

Chronotypes

Characterized by individual differences in the timing of sleep–wake schedules, biological parameters (such as core body temperature, melatonin and cortisol) and cognitive performance (such as attention).

Circadian time

A notation for the phase in a circadian cycle that represents an organism’s endogenous circadian clock, without reference to any environmental regularities or zeitgebers.

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Ruan, W., Yuan, X. & Eltzschig, H.K. Circadian rhythm as a therapeutic target. Nat Rev Drug Discov 20, 287–307 (2021). https://doi.org/10.1038/s41573-020-00109-w

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