Disruption of the clock causes pathologies

In rodents, clock function has been experimentally manipulated at different levels and by various methods. The common result of such loss-of-function studies is that disrupting the clock leads to pathology. We refer to in-depth reviews and only list a few examples here. Genetic deletion of the essential clock gene Bmal1 [14] in mice leads to various pathologies, including hyperglycemia, hyperlipidemia, increased inflammation, and premature aging [21]. Bmal1 knockout in various tissues leads to phenotypes such as hypoglycemia and dyslipidemia (in the liver) [22], metabolic inefficiency and impaired triglyceride biosynthesis (in the muscle) [23], obesity (in adipose tissue) [24], or increased inflammation and insulin resistance (in myeloid cells) [25]. Variations of such phenotypes are seen after mutation or depletion of other clock genes. Anatomical ablation of the SCN pacemaker in rodents is associated with changes in intestinal immune cells and microbiota [26], increased adiposity [27], and tumor growth [28]. Exposing mice to a chronodisruptive environment such as repeated shifts in the light–dark cycle (simulating shift work or jetlag) increases mortality in aged animals [29], promotes tumor growth [30] and autoimmune processes [31], and dysregulates inflammatory responses [32].

Epidemiological, genetic, and laboratory studies link the circadian clock to human disease

Circadian disruption due to artificial light, shift work, travels across time zones, and social jetlag (the misalignment of biological and social time) has been linked to a variety of human diseases, ranging from sleep disorders, psychiatric and cardiovascular diseases to systemic chronic inflammation, impaired immune responses against pathogens, higher tumor risk, and worsened reactions to allergens and autoantigens [3]. For example, the large epidemiological Nurses’ Health Study showed that cancer is associated with shift work and circadian rhythm disruption [33]. Shift work further increases the risk of dyslipidemia and hypertension, type 2 diabetes, heart attacks, and multiple sclerosis [34,35]. It disrupts natural rhythms of the gut microbiota, thus increasing the risk of inflammatory bowel disease [36]. Social jetlag is associated with increased alcohol and cigarette consumption [37] and a higher prevalence of obesity [37], diabetes, cardiovascular diseases, and cancer [38]. Genetic association studies indicate a role for clock genes in immune, metabolic, and psychiatric disorders. For example, variants in several clock genes (including BMAL1 and PER2) as well as in the melatonin receptor 1B (MTNR1B) gene are associated with an increased risk of specific metabolic disorders. In laboratory studies in humans, circadian misalignment leads to increased blood pressure, increased ghrelin, and decreased leptin levels, as well as reduced insulin sensitivity in skeletal muscle (for a review, see [39]).

Disease occurrence and symptoms vary with time of day

The circadian clock controls a variety of physiological processes. Thus, it is not surprising that the expression of disease symptoms often also varies with the time of day. Some prominent examples for such rhythms are symptoms in asthma, allergic rhinitis, cancer, arthritis, pain, and depression as well as the incidence of heart attacks, suicidal intent, and peptic ulcers [2]. Epidemiological studies show a steep increase in the incidence of heart attacks and strokes in the morning hours [40]. Patients with rheumatoid arthritis (RA) are particularly affected by joint stiffness and pain in the morning hours, an aftereffect of a nocturnal increase in proinflammatory cytokines [41]. In asthma and allergic rhinitis, inflammatory processes and their symptoms are highest during the second half of the night—likely due to combined direct effects of sleep loss and circadian rhythms on pulmonary and nasal epithelial functions [42]. In neurodegenerative diseases, there are rhythms in mood and emotional volatility. The “sundowning syndrome” in patients with Alzheimer’s disease is a prominent example [43]. These patients are increasingly agitated and emotionally unstable in the late afternoon or evening. On the other hand, the “dawn phenomenon” in patients with diabetes, characterized by abnormally high fasting blood glucose levels due to impaired insulin secretion, is another example for an aggravation of disease symptoms during the morning [44].

Circadian rhythms are disrupted in many pathologies

An overwhelming body of evidence shows that daily rhythms are disrupted in a wide range of diseases. Again, we can only give a few examples here. In patients with neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, or Huntington’s disease, sleep–wake behavior, melatonin secretion, and clock gene expression rhythms are all disrupted [45]. This holds true for schizophrenia spectrum and several other psychiatric disorders [46]. In patients with autoimmune diseases, daily rhythms in rest–activity, hormone, and cytokine levels, as well as molecular clock rhythms are disrupted [47]. In type 2 diabetes, circadian regulation of insulin secretion is impaired [48] and shifted eating patterns correlate with increased body mass index [49], in line with disrupted gut microbiota rhythms [8].

Exploiting the clock

In most pharmacological studies in which the time of administration is explicitly evaluated for clinical outcome, there is a clear time-of-day dependent variation in drug efficacy or toxicity [2,50–53]. This applies to drugs targeting major common diseases such as hypertension, cancer, asthma, and arthritis. This variation is explained by daily rhythms in pharmacokinetics and pharmacodynamics of most short-lived drugs [2,50,54]. For example, more than 50 years ago, HMG-CoA reductase, a rate-limiting enzyme of cholesterol synthesis, was described as being rhythmically expressed in rat liver. Its inhibitor, simvastatin, was approved some 20 years later for the treatment of hyperlipidemia with an explicit recommendation for the time-of-day to take it (“in the evening”)—one of the first chronopharmacological approvals. Timed immunotherapy in patients with melanoma has proven superior to standard therapy in terms of adverse effects and survival [55]. In RA therapy, application of a modified-release prednisone in the evening (with drug release during the second half of the night) reduces peak nocturnal interleukin-6 levels, thus positively affecting clinical parameters [42]. Such pharmacological studies are still few, although numbers have increased in recent years. Likewise, many surgical interventions can benefit from chronobiological optimization. For example, major adverse cardiovascular events are lower when aortic valve replacement is performed in the afternoon compared with morning surgeries, probably because myocardial tolerance to ischemia-reperfusion is better at this time of day [56]. Circadian effects are also important for disease diagnosis. For example, for the diagnosis of Cushing’s syndrome, which is characterized by hypercortisolemia, cortisol levels should be determined in the evening when endogenous cortisol production is at its trough [57], while adrenal insufficiency should be diagnosed in the morning when cortisol normally peaks [58].

Targeting the clock

Circadian rhythm disruption is not only a symptom, but also a risk factor for many diseases. In consequence, therapeutic approaches aimed at strengthening circadian rhythms may affect disease progression or even prevent disease initiation (Fig 3). Many zeitgebers known to influence the circadian system, such as light, food, melatonin, and exercise, have been used for this purpose [59]. Light therapy is a widely used adjunct therapy in sleep–wake rhythm and psychiatric disorders (such as depression and bipolar disorder [60]), but also in neurodegenerative disorders (such as Alzheimer’s disease and Parkinson’s disease [61]). Time-restricted eating, in which food consumption is limited to a window of 8 to 12 hours per day (without caloric restriction), improves glucose regulation, triglyceride levels, blood pressure, and various quality of life measures [62]. Exercise can phase-shift the human clock in a similar manner to light and enhance circadian amplitude of rest–activity cycles, body temperature, and muscle strength [63]. Furthermore, the circadian system can also be addressed by pharmacological means (“drugging the clock”), not only to strengthen clock rhythms, but also to address specific links between the clock and disease. Recently, several small molecule modulators of core clock function have been developed. They alter clock period, enhance its amplitude, or affect a specific clock component. For example, molecules that stabilize the clock protein cryptochrome 1 (CRY1) improve glucose tolerance in obese mice [64,65], while inhibiting casein kinase 1δ (CK1δ) prolongs clock period and may be used to treat (F)ASPS [66]. Of note, however, none of these molecules has yet been shown to be effective in humans.

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Fig 3. Circadian medicine in ICUs.

Critically ill patients frequently exhibit disturbed or absent diurnal rhythms. This is likely to be a result of their illness and sedative measures but could also be related to the often-arrhythmic environment of an ICU (inadequate light exposure, parenteral nutrition, etc.). At the same time, they are arguably the best monitored patients, and vast amounts of routine clinical data are available with time courses for a variety of physiological parameters. We propose evaluating this treasure trove of information much more systematically with data science methods to detect the clock and improving light settings in the ICUs to target the clock. The analysis of clinical source data will help to characterize patients in the ICU in terms of their circadian rhythms, to identify predictors of circadian disruption as well as therapy-based improvements, and to associate circadian rhythms with clinical parameters (for example, delirium). In addition, since current ICUs do not provide adequate light settings, we have implemented a novel concept at Charité –Universitätsmedizin Berlin, consisting of a light ceiling for each experimental ICU bed that extends from the head above the patient to the patient’s feet [67]. Each light ceiling consists of multiple layers of light-emitting diodes designed to target the patient’s circadian clock. ICU, intensive care unit. Photos can be used with kind permission of GRAFT; photo credit is given to Tobias Hein.

https://doi.org/10.1371/journal.pbio.3001567.g003

Detecting the clock

In humans, the interaction of genetic disposition, age, sex, and light exposure (intensity, duration, and timing) determines the entrained phase, the so-called chronotype [17]. Since the outcome of many therapeutic interventions depends on internal circadian phase, such interventions should be tailored to the individual chronotype. The 2 main prerequisites for successful application of circadian precision medicine are attaining a high degree of accuracy, sensitivity, and reliability of individual circadian phase assessment in clinical practice and a reasonable cost and practical applicability. Chronotype is traditionally determined by questionnaires, actigraphy, or by determining the timing of the evening rise in melatonin levels in blood or saliva [68]. Recently, more practicable biomarkers have been suggested that use single blood or tissue samples instead of time series analyses, which may allow the determination of chronotype in larger cohorts [69]. In addition, we anticipate that wearables and telemedicine will increasingly contribute to circadian diagnostics, prevention, and health maintenance. Future challenges include the use of clinical source data to characterize patients in hospitals with regard to their circadian rhythms (Fig 3), as well as the development of new diagnostic tools for circadian disruption. For example, shift work probably leads to internal desynchronization of tissue clocks, which has been very difficult to measure in animal models and virtually impossible in humans.

How can circadian clock function and rhythms be measured in clinical settings?

Traditionally, daily rhythms are captured by measuring many data points over one or more 24-hour cycles. In some clinical settings, this is possible (for example, in intensive care units), but for broader application, simpler solutions such as wearables are needed. New biomarkers can already infer circadian phase (chronotype) from a single biosample, but such tests are not yet available for detection of circadian changes in patients. Genetic markers may additionally be used to infer rhythm alterations in certain clinical settings.

How can circadian disruption be defined and quantified?

Many stressors in our modern society can affect circadian rhythms and “circadian disruption” is an umbrella term for very different modes of circadian alterations. Conceptually, one could distinguish at least 3 possible scenarios that are not mutually exclusive. The first is loss of rhythms or reduced rhythm amplitudes. The second is internal desynchronization, for example, different tissue clocks running with altered phase relationships. This is predicted when zeitgebers (such as light and food) are inconsistent (as may be the case with shift work). The third is circadian misalignment, for example, when internal synchrony is maintained but social demands do not match with internal time (such as when school starts too early for adolescents with late chronotypes). A common language is needed, and better tools to qualitatively and quantitatively describe circadian disruption under different conditions.

How does circadian disruption affect disease risk?

How exactly do shift work or other circadian disruptions contribute to a higher risk of diseases? What are the molecular and cellular mediators? How does clock disruption interact with other factors such as sleep loss, a lack of light exposure, increased stress, or unhealthy diets? Experimental protocols that aim to separate the effects of the circadian system from those of other factors are extremely challenging. We predict that in most cases where circadian medicine leads to positive health outcomes, circadian rhythm modulations exert a joint, synergistic influence on behavioral and physiological parameters together with other effectors such as caloric restriction or improved sleep.

How to choose and use the right circadian medicine approach?

To date, there are almost no recommendations or evidence-based guidelines on which type of circadian medicine should be used for which pathology, because evidence on the mechanisms of action is still sparse and no randomized controlled trials have been conducted.

How can chronobiology inform personalized medicine?

People are genetically different with regard to their circadian clocks and downstream physiology. However, the chronotype of patients has so far not had a role in the design of treatment. With simpler diagnostic methods for circadian characterization, this could change, and a truly individualized precision circadian medicine could be established.

In summary, it is becoming increasingly clear that circadian medicine has unambiguous health benefits over standard care. However, it is still far from being part of routine medical practice [70], and to truly advance circadian medicine, coordinated action is needed at different levels (Fig 2). In particular, there is still a lack of systematic and mechanistic evidence and overarching transdisciplinary chronomedical concepts. It is time to fill these gaps in order to make circadian aspects an integral part of translational research and clinical practice.