Timing matters: New tools for personalized chronomedicine and circadian health

The circadian brain and body clocks are essential to human health and well-being. Misaligned or disrupted clocks are common in modern society and are associated with numerous, highly prevalent, population diseases such as metabolic syndromes, cancer, psychiatric disorders and cardiovascular pathologies.1 Moreover, time-of-day adapted therapy (chronotherapy) has often been proven to be superior over standard therapy. Within just a few years, a new innovative (sub-) field of physiology and medicine has emerged—chronomedicine, which has greatly improved our understanding of the role of internal clocks for health and disease. However, until recently, one key barrier prevented widespread adoption of time-of-day-dependent therapeutic approaches, ie the lack of an easy diagnostic assay for measuring internal time in humans. Now three teams of scientists reported on methods to read a person's internal time from blood samples—a big step for the advance of chronomedicine.2-4 Circadian rhythms are ubiquitous, and many fundamental aspects of human physiology, metabolism, and behaviour oscillate within a 24-hour period. Circadian rhythms can be found at all levels from cells and tissues to organs, and to the entire organism. The circadian master clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and governs the daily sleep and wake rhythm, body temperature, hormone secretion (eg melatonin, cortisol, testosterone), and much more.1 Given the omnipresence of circadian rhythms, it is not surprising that especially short half-life time drugs reveal a strong time-of-day-dependent variation of their metabolic (pharmacokinetics) and physiological effects (pharmacodynamics). Approximately 50% of current drugs target the product of a circadian gene,5 and in 75% of chronomedical clinical trials (78 out of 105) published within the last 50 years a time-of-day dependency for medical treatments such as allergy, asthma, hypertension, arthritis, cancer, and cardiovascular disease was reported.6 Therefore, the outcome effect of many therapeutic interventions can be highly time-of-day-dependent. There is also a clear time-of-day relationship, eg for survival after open-heart surgery, wound healing, antibody response to vaccination, the efficacy and tolerability of chemotherapy, treatment of asthma and rheumatoid arthritis, or the use acetylsalicylic acid in cardiovascular disease. The efficacy and tolerability of a drug or any other therapy often substantially depend on the optimal time of day. Despite these vast beneficial effects, it seems astonishing that chronomedical approaches are not more successful and widespread, and have not yet found their way into daily medical and therapeutic practice. One reason is that any medicinal or therapeutic application depends not so much on external (clock) time, but on internal (body) time of an organism. Internal time is not the same between individuals because their endogenous circadian clocks have different phase relationships with respect to external clock time, which is well known for example from different chronotypes, colloquially termed "night owls" (evening types), or "morning larks" (morning types). Extreme morning types choose bedtimes and wake times which are at least 4 hours earlier than those in extreme evening types. Internal time also depends on a number of other factors, such as age, gender, genetic predisposition, season, location in the time zone, light exposure, and work schedules. Despite these different phase relationships between internal vs external clock times, physiological and psychological functions are similarly directed towards a high-quality night's sleep and a well-consolidated waking phase during the day in all chronotypes. Being synchronized with the environmental light-dark cycle, though at different phase angles, a phenomenon also known as circadian entrainment [ie the stable phase relationship between internal oscillator(s) and external "Zeitgeber"] is a prerequisite for general health and well-being. Another reason why internal time matters is increasing knowledge that misaligned or disrupted circadian rhythms are very common in our modern 24/7 society and are by far not restricted to (night) shift workers, but are also present in different age groups within the general population. These circadian disruptions may per se be associated with higher prevalence for numerous common population diseases, such as metabolic syndromes, cancer, psychiatric disorders and cardiovascular pathologies. A major problem in determining internal circadian time is the lack of accessibility and direct manipulation of the circadian master clock inside the human brain, in the SCN. Therefore, indirect markers of the pacemaker function (to the best of knowledge) are used to assess its phase (and its response to environmental stimuli). To date, assessment of the pineal hormone melatonin secretion onset in the evening is one of the most widely used methods for circadian phase determination in humans. The dim light melatonin onset (DLMO) relates to the clock time when melatonin concentrations in saliva or blood raise beyond a predefined threshold concentration, which in entrained individuals occurs in the evening, or early night respectively. To determine this threshold, several samples are required in the time range of 5-6 hours before the usual bedtime of an individual. In addition, sampling must be performed under controlled dim light condition because light suppresses endogenous melatonin secretion. Hence, the current gold standard method for circadian phase determination is a tedious, complicated and costly procedure, which cannot be performed in a routine doctor's office at normal consultation hours. In recent years, several attempts were made to tear down this key barrier preventing widespread adoption of time-of-day-dependent therapeutic approaches. The general approach in humans, known from at least three different groups is measuring time-of-day-dependent gene activity from RNA of different blood cells2-4 after taking one2, 3 or two4 blood samples, and combine it with machine learning approaches. These approaches allow to indirectly predicting circadian phase of the master clock in the SCN. Two of three groups have determined circadian phase against the gold standard, the DLMO.2, 3 One critical endpoint of such an endeavour is its precision, which depends on the molecular biological method as well as on the machine learning tool. So far, the approach by Wittenbrink et al3 (BodyTime) is the one with the highest accuracy with respect to the DLMO, the deviation of the two methods is only ~0.5 h. The group of Laing et al in fact had tested their method also in individuals with disrupted sleep-wake rhythm, but the accuracy of their approach was lower (≤2 h)2 and therefore, the future challenge will be to create a high accuracy internal time prediction approach, similar to that by Wittenbrink et al which is reliably applicable in all individuals, with or without chronodisruption. In summary, most therapeutic interventions are time-of-day-dependent and must be individually tailored. The two main prerequisites for successful application of circadian precision medicines are (1) high accuracy, sensitivity and reliability of individual circadian phase assessment in the clinic and (2) its practical applicability. The recently emerging diagnostic tools now allow an objective readout of internal time in individuals and enable, eg (i) to stratify cohorts in clinical studies according to internal time (pharmacokinetics and -dynamics of many drugs are time-of-day-dependent); (ii) to personalize chronotherapy according to individual internal time (chronotype); (iii) to distribute shift workers to day/night shifts according to chronotype to minimize/mitigate clock disruption; (iv) to develop treatment strategies for patients with attenuated internal rhythm regulation (eg ICU patients, neurodegenerative disease patients, elderly people); (v) to learn more about the interaction of the circadian system with population diseases (Figure 1). There is no conflict of interest.