Abstract
1 Circadian rhythms and the age of chronotherapy in humans
Circadian rhythms are oscillating biological processes with a rough 24‐hour period and ubiquitously exist in most organisms living on the surface of the earth. These rhythms are manifest of the cycling transcriptome which is driven by the endogenous circadian clock. Given the clock orchestrates half of protein‐coding genes and most physiologies in humans, it is no exaggeration to say: we are what our clock ticks. Therefore, human health lies in a harmonic relationship between our body clocks and the environment. Despite a great advancement in the molecular mechanism of the circadian clock in the last few decades, investigations on the circadian clock in human health have just emerged [1].
2 Circadian phase, a key point for chronotherapy
Three parameters are involved to describe a circadian rhythm: period, amplitude and phase. Circadian period and amplitude reflect the speed and robustness of circadian rhythms, respectively. These properties are relatively resilient to environmental perturbations. Circadian phase, however, imitates the synchronization of the endogenous clock to the environment, and has a well‐documented relationship to human health in modern society.
There are several reasons why the circadian phase is the key point for application of chronobiology into human health. First, numerous genes involving drug efficacy and toxicity are under circadian regulation [2], therefore it is necessary to examine the time of day effect of a medicine, even in the early, pre‐clinical stage of drug development. Second, acute and chronic misalignments of circadian phase with the environment are the major reason for circadian clock‐related disorders. For example, jet‐leg causes sleep problems and chronic shift‐work/night eating causes sleep and metabolic disorders. Chemical screens to identify small molecules directly targeting the circadian phase will be the potential therapeutic approach. Recently, a paper authored by Ju et al. reported that a natural compound, cordycepin, dramatically induces "type 0" phase shifts in mammalian cells and animals [3], while its clinical relevance needs further evaluation. Third, although we live in and follow the same solar/social time‐schedule, each individual person has a unique chronotype for his/her own. Chronotypes reflect the impact of environment on human physiology schedule due to the different phase angle between our endogenous clocks and the solar/social rhythms. People with extreme chronotypes suffer long‐term phase misalignment and therefore tend to be more vulnerable to diseases. As an example, two review papers here in this journal well summarized the association of the circadian chronotype with various mental and neuro‐degenerative disorders [4, 5].
3 Human chronobiology and future directions
Extreme chronotype is the most common form of circadian phase misalignment in daily life. The research paper by Liu et al. showed a near‐normal distribution of chronotype in Chinese population [6]. Interestingly, there is an apparent shift from morning to extreme morning in the young and aged people, and evening to extreme evening at the age of 20–40 which is the main source of social labors. Chronotype may need to be taken into account when planning a school or work schedule. The mechanism gating human chronotype is largely unknown, while its changes with age require further examination. Besides, the phase angle among tissues in different chronotypes and its causal relationship with diseases still needs to be investigated. Furthermore, a more accurate protocol to monitor chronotype is also necessary before it becomes a consideration in clinical therapy. Wu et al. summarized the recent gold‐standard method of investigating circadian transcriptome [7]. Taking advantage of circadian transcriptome analysis, a non‐invasive and accurate chronotype monitoring method will be developed in the future.
In summary, this preview is a synopsis of the association between the circadian clock and human health. Much work is still needed to enter the great age of circadian translational medicine.