Time for circadian medicine
Achim Kramer
Abstract
Circadian medicine developed from chronobiology, which deals with temporal processes in biological systems. Humans have an internal circadian clock that it is genetically determined, synchronized with the environment by light and food, and controls myriad time-of-day-dependent physiological processes in each cell of our body.1, 2 In 2017, Rosbash, Hall and Young received the Nobel Prize in Physiology or Medicine for elucidating the molecular mechanism of the circadian clock. In addition, the incidence and symptoms of many diseases vary with the time of day. Shift work and other environmental factors disrupting our clock are associated with common diseases. Vice versa, various maladies perturb physiological rhythms, such as the sleep–wake cycle. Chronobiology allows us to study such relationships mechanistically, for example by genetic models. The evidence is now overwhelming: An intact, well-synchronized circadian clock is crucial for health. Modern environmental factors such as shift work, travel across time zones, irregular diet, light pollution or social jetlag are on the rise in our 24/7 society and increase the risk of disease by disrupting or misaligning the circadian clock. Moreover, in many pathologies, circadian rhythms are disturbed, thus a disrupted clock may also be a symptom of disease. Because of multiple feedbacks, circadian disruption and disease are linked in a kind of self-enforcing vicious cycle.3 Fortunately, these correlations are gradually being recognized, and a new discipline of “circadian medicine” is being established that aims to use and translate this knowledge for the benefit of patients. Circadian medicine is increasingly promoted in high-profile medical journals4-6 and standard medical books7 and centres and clinics are emerging around the world. There are already first great successes, for example, in the chronotherapy of cancer8 or rheumatoid arthritis9 or—just recently—in the development of novel diagnostic tools.10, 11 Circadian medicine comprises three fundamental aspects, which we have called the triad of circadian medicine: detecting the clock, targeting the clock and exploiting the clock.12 (i) Detecting the clock means the development of circadian medicine as part of precision medicine through new diagnostic tools that allow personalized interventions tailored to the status of the circadian clock. For example, new objective biomarker tests have been recently proposed that require blood or tissue samples of only a single or few time points, which may allow diagnosing circadian rhythms in larger cohorts.11, 13 In addition, the increasing use of wearables and telemedicine will enable a live readout of the clock in the future, thus becoming very important for preventive medicine. (ii) Targeting the clock means the improvement or re-synchronization of disrupted rhythms through interventions in the clock. Such interventions can look very different, for example, light therapy, the use of the dark hormone melatonin, and time-restricted eating (TRE) as a zeitgeber, especially for clocks in peripheral organs or exercise. Also, initial studies are underway that directly target the molecular clock using drugs. Underlying all these approaches is the hypothesis that strengthening or realigning the circadian clock reduces the risk of and accelerates recovery from disease. (iii) Exploiting the clock means the usage of knowledge about physiological rhythms for time-of-day adapted treatment regimens or diagnostic procedures. For example, many drugs, especially those with short half-lives in the body, exhibit a time-of-day dependent difference in their effects and side effects, which is still largely ignored in clinical practice. In about 75% of pharmacological studies in which the time of administration was explicitly evaluated for clinical outcome, a time-of-day dependent variation in drug efficacy or toxicity was demonstrated.4 The reviews presented in this special issue address all these three aspects of circadian medicine. They do so from the perspective of different disease patterns, because there are likely to be overarching principles for the reciprocal relationship between circadian system disorders and disease, and uncovering these common principles requires broad transdisciplinary research. This special issue attempts to address this fact and includes review articles on many different disease conditions and their relationship to the circadian clock, as well as treatment options using circadian medicine approaches. Our current knowledge of the impact of the circadian clock on pathologies and vice versa is addressed, and ways and strategies of treating them with circadian medicine approaches are presented. Finally, one of the reviews explicitly addresses the challenge of data integration and analysis in circadian medicine questions and projects, which is an intersecting theme for the field as a whole.14 Despite the deliberately chosen breadth in the subject matter, there are still three main areas that the reviews are focused on: circadian immunology, circadian energy metabolism and circadian neuropsychiatry. The field of circadian immunology goes back over 50 years, when it was first reported that circulating lymphocyte counts oscillate in healthy humans in a time-of-day dependent manner and that endotoxin susceptibility of mice depends on exposure time. Since then, hundreds of experimental and epidemiological studies in rodents and humans have shown that the circadian clock regulates immunity at almost all levels (e.g., migration of myeloid and lymphoid cells, cytokine secretion, differentiation and maturation of leukocyte subsets) and that this regulation is reciprocal (for comprehensive reviews, see Refs. [15-17]). For example, disruption of the circadian clock leads to abnormal development of Th17 cells, resulting in higher susceptibility to experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.18 It is also important to note that sleep per se increases an organism's resistance to infection and that sleep deprivation impairs many immune functions.19 Therefore, it is often not easy to determine whether compromised immunity is a direct result of circadian dysregulation or indirectly caused by insufficient sleep. In 2019, the National Institutes of Health (NIH) recognized these developments and hosted an interdisciplinary workshop titled “Sleep Insufficiency, Circadian Misalignment, and the Immune Response” to discuss the current state of knowledge and recent findings in this field, thereby stimulating translational approaches.20 In this special issue, the interplay between the circadian clock and the immune system and the potential of circadian medicine for treatment is discussed in the context of inflammatory autoimmune diseases such as rheumatoid arthritis and multiple sclerosis21 as well as in lung inflammation22 and Alzheimer's disease.23 The interaction between circadian clocks and metabolic functions is complex and intensively studied at many levels.24 It became clear early on that systemic circadian control of metabolic processes is mediated by a sophisticated interplay between the central clock and peripheral clocks in metabolically relevant tissues (liver, adipose tissue, muscle, pancreas, adrenal, etc.). With the discovery that nutrients and metabolites, in turn, can act as powerful zeitgebers for peripheral clocks, and that malnutrition or food intake at the wrong times leads to disruptions of the circadian system, the idea was born that TRE could be used as a circadian medicine approach to restore normal rhythms (especially in peripheral tissues). Indeed, TRE shows significant improvement of metabolic parameters not only in mice, but also in humans, which also occurs when strict attention is paid to not reduce caloric intake. In this special issue, the interplay between the circadian clock and metabolism as well as the potential of timed nutritional cues to improve metabolic health is covered by several review articles, for example, in the context of non-alcoholic fatty liver disease,25 multiple sclerosis,21 obesity26 and intensive care unit patients.22 In addition, exercise as a zeitgeber and its effect on myokine and microRNA release in type 2 diabetes patients is discussed.27 The master clock of mammals is located in the suprachiasmatic nuclei of the anterior hypothalamus and is entrained via retinal innervations. Before the discovery of peripheral oscillators, chronobiology was usually studied in neurobiology departments. Many neurodegenerative processes,28, 29 such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and also psychiatric disorders (e.g., major depressive disorder, bipolar disorder, and schizophrenia30, 31) as well as brain failure resulting in neurocognitive disturbances (e.g., delirium32) are characterized by substantial changes in circadian rhythms, including the sleep–wake cycle. Since circadian rhythm and sleep disturbances frequently precede cognitive decline, they have been postulated as risk factors or predictors for these diseases. On the other hand, the neural circuits that regulate sleep and circadian rhythms are vulnerable to neurodegeneration and brain damage, so disruption of circadian rhythm may also be a consequence of these diseases. Thus, the relationship between circadian rhythm, sleep and neurological or psychiatric disorders is complex and likely bidirectional. Uncovering the fundamentals of this relationship will provide opportunities to identify targets for the prevention and treatment of these debilitating diseases. In this special issue, reviews focus on neuropsychiatric disorders such as Parkinson's disease,33 Alzheimer's disease,23 multiple sclerosis,21 delirium,22 psychosis,34 and addiction.35 In summary, this review series aims to demonstrate the ubiquity of the influence of the circadian clock and its disruption on health and disease, thereby contributing to the identification of the overarching principles that link the circadian clock and pathology in various organ and disease systems. This is a prerequisite for developing and testing evidence-based circadian medicine strategies for clinical application—concepts and initial successes are presented here. The vision for the future of circadian medicine is to integrate it firmly into medical guidelines so that, for each patient, the circadian aspect is always taken into account and, if necessary, included in the treatment plan. Circadian medicine has many facets and to sustain its development, they all need to be advanced. The author is a consultant for Stanford University and a shareholder of BodyClock GmbH.