Training the Circadian Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases

Sulli G, Manoogian ENC, Taub PR, Panda S. Training the Circadian Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases. Trends in Pharmacological Sciences. 2018 Sep;39(9):812-827. DOI: 10.1016/


Although circadian rhythm disruption (CRD) was typically considered to be a risk for chronic diseases solely for shift workers (∼20% of workforce), new epidemiological data suggest more than 80% of the population may be living a shift work lifestyle and thus are at elevated risk for chronic diseases.

Acute CRD compromises health with temporary physical challenges and may be a trigger for underlying latent diseases. Chronic CRD raises the risk for cancer along with a range of diseases affecting the central nervous system, immune and reproductive systems, metabolic organs, endocrine functions, and cardiovascular health.

Recent progress in understanding the molecular mechanisms of circadian timing and diurnal rhythms of tissue-specific gene products has generated testable hypotheses for how the circadian timing system optimizes health and, conversely, how circadian disruption leads to diseases.

Leveraging circadian rhythms to prevent, manage, and treat diseases involves three major strategies: optimizing the circadian lifestyle (‘training the clock’), optimizing timing of therapies (‘clocking the drugs’), and targeting specific circadian clock components (‘drugging the clock’).

Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management. In modern societies light at night disrupts circadian rhythms, leading to further disruption of sleep-activity and eating-fasting cycles. While acute circadian disruption may cause transient discomfort or exacerbate chronic diseases, chronic circadian disruption can enhance risks for numerous diseases. The molecular understanding of circadian rhythms is opening new therapeutic frontiers placing the circadian clock in a central role. Here, we review recent advancements on how to enhance our circadian clock through behavioral interventions, timing of drug administration, and pharmacological targeting of circadian clock components that are already providing new preventive and therapeutic strategies for several diseases, including metabolic syndrome and cancer.

© 2018 Elsevier Ltd. All rights reserved.

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