CC BY
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Weinert D., Gubin D.G.
Institute of Biology/Zoology, Martin Luther University, Halle-Wittenberg, Germany Tyumen State Medical University, Tyumen, Russia
Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, Russia
THE CIRCADIAN BODY TEMPERATURE RHYTHM -ORIGIN AND IMPLICATIONS FOR HEALTH AND WELLBEING
The aim of the present review is to characterize the circadian body temperature rhythm of humans, a well-established marker of the circadian system and its origins. Some results of experiments on animals are also mentioned as they show general biological principles. The relevance of the circadian body temperature rhythm for health and wellbeing is described together with examples of its distinct alterations in association with certain pathologies. Since the circadian body temperature rhythm varies depending on stages of individual development, ontogenetic and age-dependent changes, their causes and consequences are also considered. Finally, some ways to prevent or minimize consequences of disruptions of the circadian body temperature rhythm are discussed.
Keywords: body temperature, circadian rhythm, circadian disruption, humans, mammals, health, disease, age, melatonin.
Introduction. In homeothermic organisms including humans, the body temperature has to be maintained within a narrow range to facilitate optimal functioning of physiological processes. Complex homeostatic mechanisms compensate effects of thermal load and loss. As a consequence, body temperature varies slightly around a set point. In addition, it changes in the course of the day due to rhythmic input from an endogenous clock. Body temperature rises during the active period of an organism and falls during its rest.
Biological rhythms are an inherent property of living systems. Physiological phase relationships between different rhythmic functions and a proper phasing with respect to the cyclic environment constitute their internal and external temporal order. Circadian rhythms deserve special attention here as they enable an organism to adapt to the day-night changes and to prepare for, rather than merely react to, cyclic events in the environment. The appearance of reproducible and stable circadian rhythms of high amplitude, and with a characteristic phasing with respect to other biological processes and the external environment, is believed to guarantee an optimal functioning of the biological system, with maximum efficiency, performance and welfare (Waterhouse, DeCoursey 2004). Any disturbances of this temporal order, so-called circadian disruptions have consequences for subjects' performance and wellbeing and may cause several diseases (Escobar et al. 2011; Polidarova et al. 2017; Sharma et al. 2015; Vaze, Sharma 2013; Waterhouse, DeCoursey 2004; Yadav et al. 2017).
In mammals including men, the suprachiasmat-ic nucleus (SCN), located in the anterior hypothalamus, immediately dorsal to the optic chiasm, is accepted to be the central circadian pacemaker (Weaver 1998). It generates self-sustained oscillations via a number of feed-back loops where clock proteins control the transcription of their own genes (Albrecht 2004; Ko, Takahashi 2006; Rep-pert, Weaver 2002). Also for several other brain regions and peripheral organs like the liver, kidney, lung, heart, muscle and others it has been shown that they do generate self-sustained oscillations, which normally are under the
control of the SCN however (Reppert, Weaver 2002; Schi-bler et al. 2003).
Since the period of the rhythms generated in the SCN differs slightly from 24h, a continual correction by environmental periodicities, termed «zeitgebers», is necessary. In mammals, this is mainly by the light/dark cycle (Aschoff 1954, 1960; Golombek, Rosenstein 2010). Initially, it was supposed that humans are an exception here and that social factors are more important. However, it could be shown that the light-dark cycle is the most relevant zeitgeber also for men (Duffy et al. 1996; Minors et al. 1991).
The SCN controls body functions and peripheral rhythms by means of neural and humoral signaling pathways (Cheng et al. 2002; Kramer et al. 2001, 2003; LeSau-ter, Silver 1998). Also, the body temperature rhythm may transfer information to peripheral systems, thus acting as an internal zeitgeber (Brown et al. 2002; Buhr et al. 2010; van Someren 2000; Weinert 2005b).
The aim of the present review is to characterize the circadian body temperature rhythm of humans, as a well-established marker of the circadian system (for references, see (Weinert, Waterhouse 2017) and to elucidate its origin. Some results of experiments on animals will be mentioned as they show general biological principles. In the second part, the relevance of the circadian body temperature rhythm for health and wellbeing will be described. Here also, ontogenetic and age-dependent changes, their causes and consequences will be mentioned. Finally, some ways to prevent or minimize consequences of disruptions of the circadian body temperature rhythm will be discussed.
Origin of the body temperature rhythm: endogenous and exogenous components. The core body temperature of humans and of homeothermic organisms in general, is regulated by a complex system including homeostatic and circadian components. On the one hand, a «set point» exists, a value at which the core temperature is kept by a thermoregulatory center located within the preoptic anterior hypothalamus (Hammel 1968; Satinoff 1978). This latter consists of two groups of neurons, instigating heat loss or heat gain mechanisms. As a consequence, the core body temperature is maintained at a rather stable lev-
el, in spite of a wide range of ambient temperatures and physical activity or during sleep (for review, see Reilly, Waterhouse 2009; Waterhouse et al. 2005).
The circadian changes in core temperature on the other hand are probably due to a rhythmic input from the SCN modulating the set point and altering the thresholds for cutaneous vasodilatation and sweating (Aizawa, Cabanac 2002; Aschoff 1983; Refinetti 1997; Refinetti, Menaker 1992). According to Aschoff and co-workers (Aschoff et al. 1972), two processes are involved facilitating a highly efficient tuning of the body temperature rhythm - circadian changes in heat production and heat loss with the rhythm of heat production being phase-advanced with respect to the rhythm of heat loss. As long as heat production surpasses heat loss core body temperature increases, thereafter it starts to fall.
Under resting conditions in thermoneutral environments, it is mainly mechanisms of heat loss that are involved, by controlling the cutaneous blood flow and the rate of sweating of the extremities (Aschoff et al. 1972; Krauchi, Wirz-Justice 1994; Refinetti, Menaker 1992; Reilly, Waterhouse 2009; Waterhouse et al. 2005). The contribution of metabolic heat production to the observed circadian rhythm at rest has been found to be much less (Aschoff et al. 1972; Reilly, Brooks 1982). In humans, there is a circadian rhythm of heat loss from the distal limbs, with rhythms of skin temperature and blood flow in these regions showing peaks in the late evening and minima in the morning (Aschoff et al. 1972; Krauchi, Wirz-Justice 1994; Smolander et al. 1993). Melatonin appears to make a contribution to these changes, thereby being involved in the regulation of the core body temperature rhythm (Krauchi 2002). The rate of melatonin secretion increases in the evening, and this promotes a fall of core body temperature via cutaneous vasodilatation. In the morning, the opposite changes take place (Cagnacci 1997).
In addition to the described endogenous components, exogenous components are involved in the expression of the overt body temperature rhythm. A strong impact has the sleep-wake cycle, with sleep and its associated change in posture producing a fall, and both physical and mental activities producing rises (Waterhouse et al. 1999a; Waterhouse et al. 2001a; Waterhouse et al. 1995). Moreover, thermoregulation differs between sleep stages. Core body temperature is decreased, while peripheral temperature is increased, during the non-REM stages (Burgess et al. 2001; Krauchi, Wirz-Justice 1994, 2001). Waterhouse and co-workers found a fall of rectal temperature following slow-wave sleep and an increase after REM phases (Waterhouse et al. 1995). As a consequence of sleep related behaviors, «lying down» and «relaxation after lights off», distal skin blood flow and thus distal skin temperature increase: as a consequence, core body temperature declines (Krauchi 2007).
The described interactions are an essential part of humans' temporal order (see also below). That is, the circadian rhythm of body temperature is normally timed to be in synchrony with specific phases of the sleep-wake cycle, the pineal melatonin rhythm, and the responsiveness of
the circadian pacemaker to light. As a result of this, in the evening, the clock-mediated fall is accentuated by the fall in activity and lighting and by the onset of melatonin secretion. In the morning, the opposite changes take place; the morning rise of core temperature that is due to the body clock is augmented by the change from sleep to waking, the increase in ambient illumination, and the fall in melatonin secretion. Moreover, the rhythm in core temperature is promoted by behavioral changes. In diurnal species, these not only include increases in motor activity during the morning and decreases during the evening; there is also a preference for warmer ambient temperatures in the morning and cooler ones in the evening (Refinetti 1998). In humans, there is an additional effect due to the change in posture on retiring to bed, that «un-loads' the cardiovascular system and reduces sympathetic tone (Krauchi, Wirz-Justice 2001). At the same time, the described interactions are often called «masking», as they produce deviations from the endogenous circadian rhythm, generated by the central pacemaker. Hence, the estimates of phase and amplitude taken from the overt rhythm are not correct in most cases, and this may lead to misinterpretation (Weinert et al. 2002a; Weinert, Water-house 2007; Weinert et al. 2002b).
Methods have been developed to separate endogenous and exogenous components and thus to characterize the endogenous rhythm which reflects the body clock (Waterhouse et al. 2000a; Weinert, Waterhouse 2017). In adult humans, a protocol known as «constant routine» is used very often and considered by many authors as the «gold standard» (Czeisler et al. 1985; Duffy, Dijk 2002; Mills et al. 1978). It removes the masking effects at source by preventing sleep, by maintaining constant the environment and physical and mental activities, and by giving the subject identical meals at equi-spaced intervals. However, this protocol is inconvenient, and quite unsuitable for repeated measurements on several days or for studies on babies and animals, for example. Also, the experimental conditions during a constant routine protocol are highly artificial. Therefore, several alternatives have been developed (Waterhouse et al. 2000a; Weinert et al. 2003; Weinert, Waterhouse 1998, 2017). With these alternatives, the data can be collected under natural conditions, as the effects of the sleep-wake or rest-activity cycles are removed later mathematically. These so called «purification» methods not only provide a good estimate of the endogenous rhythm but also describe formally the effect of the environment and the rest-activity cycle via calculation of the gradient of the relationship between temperature increase and spontaneous activity. The latter acts as an indicator of thermoregulatory efficiency or the «sensitivity» of ther-moregulatory reflexes. The methods have proven successfully in many studies on humans (Waterhouse et al. 2001c; Waterhouse et al. 1999b; Waterhouse et al. 2000a; Water-house et al. 2000b; Weinert et al. 1994) and on rodents (Schottner et al 2011; Weinert et al. 2003; Weinert, Water-house 1998; 2007).
To measure core body temperature as a marker of the SCN, rectal probes has proved to be useful in the labo-
ratory under «constant routine» conditions (Czeisler et al. 1985; Mills et al. 1978; Weinert, Waterhouse 2017). However, under field conditions, when living normally, a rectal probe might be uncomfortable and cause hygiene problems. More acceptable methods include the use of tympanic membrane and sublingual temperature measurements. But this does not allow data collection when subjects are asleep. Edwards and colleagues did investigate some alternatives (Edwards et al. 2002). They analyzed temperature data obtained with a rectal probe, a temperature pill swallowed by the subjects and an insulated skin sensor placed under the axilla. Simultaneously, subjects' activity was measured using a wrist actimeter. While the daily means were different, the three temperature records showed similar phases and amplitudes. However, in the case of axillary temperature, the relationship between activity and its thermogenic effect was not reliable. As a consequence, purification was not successful and did not provide a good estimate of the endogenous body temperature rhythm. Interestingly, in newborn babies, skin temperature measurements are applicable. Because of their very limited motor activity and the good insulation from bedclothes, a close parallelism between rectal and skin temperatures does exist (Weinert et al. 1994).
Madrid and co-workers suggested insulated wrist temperature as being reliable to evaluate circadian rhyth-micity (Ortiz-Tudela et al. 2014; Sarabia et al. 2008). However, this temperature does not characterize the phase of the endogenous clock. The decrease in rectal temperature is preceded by an increase in extremity temperature by about 4 hours, because the variation in extremity skin blood flow is involved in the regulation of the circadian core temperature rhythm (Smolander et al. 1993). Moreover, the exogenous components due to varying environmental temperatures for example are considerable.
Relevance of the body temperature rhythm for health and wellbeing. In addition to proper phase relationships of circadian rhythms with the periodic environment, the so-called «external temporal order», interactions between different rhythms exist what leads to mutual stabilization and physiological phase relationships, and is called the «internal temporal order». The circadian body temperature rhythm plays an important role here as it may transfer information from the SCN to peripheral systems, and to particular peripheral oscillators. Brown and co-workers (Brown et al. 2002) have shown that a temperature rhythm of amplitude equal to that of the endogenous body temperature rhythm though being incapable of establishing circadian gene expression de novo, can maintain previously induced rhythms. Accordingly, the body temperature rhythm must be considered as an internal zeitgeber, synchronizing different circadian functions and, particularly, peripheral oscillators of organisms.
The circadian rhythm of core temperature is associated with rhythms of sleep propensity (Dijk, Czeisler 1995), physical performance, and mental performance (Reilly et al. 2007; Waterhouse et al. 2005; Waterhouse et al. 2001b). Humans normally fall asleep when core body temperature is decreasing, and their main sleep period ends on the ris-
ing part of the circadian temperature curve. However, it is not the core body temperature but the temperature of the skin, especially of extremities, which is causally involved in the modulation of sleep propensity. Alterations in skin temperature over the course of a day modulate neuronal activation in arousal-related brain structures and thus provide a third signaling pathway for the circadian modulation of sleep, in addition to synaptic and neurohumoral pathways (van Someren 2004). Also a manipulation of skin temperature within the normal circadian range has an effect on the sleep-onset latency and vigilance (Raymann et al. 2005; Raymann, Van Someren 2007).
The fall of core temperature at the end of the waking period is caused by distal vasodilatation. This leads to a warming up of extremities which, in turn, induces sleepiness. The opposite changes take place at the end of the sleep phase; the distal vasoconstriction reduces heat loss leading to an increase of core temperature and, at the same time, the temperature of the extremities falls to provide a signal to wake up. Via these mechanisms, the circadi-an body temperature rhythm is involved in the regulation of the sleep-wake cycle (Boivin et al. 1997; Krauchi 2007; Rayman et al. 2005; van Someren 2000, 2004).
Disrupted circadian body temperature rhythms may cause sleep problems or various pathologies. Though, the underlying mechanisms are different. Changes in the central pacemaker and the mechanism of entrainment by periodic environmental cues or deficits in the thermoreg-ulatory system can be involved. Studies on animals and humans have shown that the SCN does function at very early ontogenetic stages and until the very last days of life (Gubin et al. 2016b; Weinert 2005a, 2010). Newborn babies, even those born preterm, show a clear circadian body temperature rhythm at the 2nd day of life already. As a circadian sleep-wake cycle is absent at this stage, the body temperature rhythm presumably derived from an internal body clock (Weinert et al. 1994).
Adult persons are normally well entrained to the 24-h environment. However, the endogenous period length may be different from 24 h both in clinical setting and even in healthy subjects. In a study of Reinberg and co-workers, healthy controls as well as patients suffering from Major Affective Disorders showed a multimodal distribution of the period length of their body temperature rhythm. In controls however, the highest frequency was found for the 24-h component, while patients commonly exhibited a period shorter than 24h suggestive of a desyn-chronized time structure (Bicakova-Rocher et al. 1996). The advanced and the delayed sleep phase syndrome are also caused by deviating from 24 hours endogenous period lengths (Patke et al. 2017).
Another and probably more common reason for cir-cadian disruption is an impaired external synchronization. As already mentioned, the main zeitgeber, which entrains the endogenous rhythms to the 24-h environment is the light-dark (LD) cycle. The photic information is perceived by a subpopulation of retinal ganglion cells, the so called intrinsically photosensitive retinal ganglion cells (ipRGC). The axons of theses neurons form the retino-hy-
pothalamic tract (RHT), the main afferent pathway to the SCN (Freedman et al. 1999; Golombek, Rosenstein 2010; Markwell et al. 2010; Morin 1994). Via the RHT, the timing information, i.e. the light-dark signal reaches the SCN where it intensifies the expression of clock genes and thus entrains the SCN to the 24-h environment (Albrecht et al. 2001; Shigeyoshi et al. 1997). Any damage of ipRGCs leads to an impairment of photic synchronization.
Glaucoma is the leading cause of irreversible blindness worldwide (Weinreb et al. 2014). The high intraocular pressure damages ganglion cells, including also the number and the function of ipRGCs (Drouyer et al. 2008; Feigl et al. 2011). Accordingly, not only image forming vision but also the transmission of the photic zeitgeber signal is compromised. As a consequence, the synchronization of circadian rhythms is impaired what lead to a circadian disruption (Drouyer et al. 2008; Goz et al. 2008; Jean-Louis et al. 2008). In a study performed recently by Tatyana Malishevskaya and coauthors, a phase delay of the body temperature rhythm and its consequences for sleep quality in primary open angle glaucoma patients was shown for the first time. Both phenomena closely correlated with the degree of retinal ganglion cell loss (Gubin et al., 2018).
Very early and late ontogenetic stages also are characterized by a diminished photic synchronization of circadi-an rhythms (Sitka et al. 1994; Weinert, Waterhouse 2007). In aged organisms, the number and function of ipRGCs might be decreased. But, there are also other factors leading to an impaired photic synchronization. Because of lens yellowing and senescent miosis, progressively less visible light reaches the ipRGCs (Turner, Mainster 2008; Turner et al. 2010). This effect may be augmented by people's life-
style. Old people are very often sedentary and insufficiently exposed to daylight conditions, what contributes to the high phase variability which has been observed repeatedly (Ancoli-Israel et al. 1997; Gubin et al. 2006; Shochat et al. 2000).
Changes of the circadian body temperature rhythm may also be caused by mechanism located downstream from the SCN, particularly the system of thermoregulation may be disturbed and accordingly the thermoregulation may be insufficient. Particularly in early and late life stages, thermoregulation appears to be less effective than in adults (Waterhouse et al. 2000b; Weinert 2010). In elderly people, a decreased thermosensitivity reduces or prevents the ability to respond to slight increases in bed temperature (Raymann et al. 2007; Raymann, Van Somer-en 2008). Also, the temperature fall in the extremities gets more marked with increasing age. As a consequence, elderly subjects wake up earlier in the morning.
Deteriorations of circadian rhythms may also be the caused by various pathologies. A disruption of the circa-dian body temperature rhythm as a consequence of metabolic dysfunction was first described in the experimental model of streptozotocin-induced diabetes in Wistar rats (Ramos-Lobo et al. 2015). We found a progressive disruption of the 24-hour body temperature rhythm associated with advancing metabolic dysfunction in prediabetic and diabetic individuals, Fig.1. Namely, an increased 24-hour mean and a dampened 24-hour amplitude accompany adverse changes in metabolic state; particularly type 2 diabetes mellitus (Gubin et al. 2017). In a simultaneously published paper, it was shown that the metabolic syndrome is also associated with a dampened wrist skin tempera-
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POAG
Overweight Prediabetic Patients T2DM Patients
A Primary metabolic pathology pathology
Ophthalmologic Patients No
Stable POAG Progression POAG
B Primary neurodegenerative
Fig. 1. Distinctive daily body temperature patterns of individuals, diagnosed with different pathology; modified from Gubin et al., 2017 (A); Gubin et al., 2018 (B). Rhythm parameters (24-hour mean/MESOR, rhythm strength/amplitude and phase) are specifically modified in certain diseases, either selectively or concomitantly). T2DM - Type 2 diabetes mellitus; POAG - Primary open angle glaucoma
ture amplitude and reduced phase stability; and elevated triglycerides may serve the main biochemical predictor that provokes metabolic-disorder-associated circadian temperature rhythm disruption (Harfmann et al., 2017). Overweight might be involved here, though literature data on the relation between body temperature and body mass index (BMI) or body weight are not consistent (Adam 1989; Heikens et al. 2011; Savastano et al. 2009; Tranel et al., 2015). We found a positive correlation between body mass/BMI and body temperature. The MESOR, i.e. the daily mean estimated by COSINOR analysis, increased. This could have been the consequence of an elevated heat production and a reduced heat loss because of better insulation (Savastano et al. 2009). While healthy overweight subjects might be able to compensate this by activating heat release via less insulated parts of the body surface, e.g. the hands (Savastano et al. 2009), in subjects suffering from T2DM thermoregulation is impaired, particularly the capacity to dissipate heat via extremities is reduced (for review, see Kenny et al. 2016). Initially, distal thermoregulation is impaired mainly at night, i.e., during the sleep span (Rutkove et al. 2009) and consequently the core body temperature will not drop at night. With progressive severity of the diseases, thermoregulation obviously becomes more compromised, extending also to the awake span, which leads to a further increase of the daily mean and a decrease of the 24-h amplitude.
More generally, different diseases may have its specific signatures on temperature circadian rhythm and its parameters (see for example Gubin et al., 2017, 2018; Zhu et al., 2015). Currently accumulating databases show that certain pathologies are characterized by distinctive temperature 24-hour patterns (Fig.1). Further research is necessary to generate specific reference values, standardized for age/gender/chronotype, etc. which can be used to estimate the risk to fall ill, i.e. for early diagnosis.
Treatment of rhythm disturbances. As already mentioned, the body temperature rhythm not only is a marker for the circadian system (Waterhouse et al. 2005; Wein-ert, Waterhouse 2017), it also plays a role as an internal zeitgeber and stabilizes the phase relationships between different rhythms. Accordingly, stabilizing the body temperature rhythm will stabilize also the temporal order in general with positive consequences for health, wellbeing and the overall quality of life (Gubin, Weinert 2016).
A good candidate to treat rhythm disturbances is me-latonin. This is known to have chronobiotic properties, and has been used to treat circadian desynchrony in blind people, circadian disorders of sleep and mood, and maladaptation to shift work and to trans-meridian air travel (Arendt, Skene 2005; Lewy et al. 2005; Redfern et al. 1994; Sack, Lewy 1997). Lewy and coworkers (Lewy et al. 1992) were the first to show that orally administered me-latonin shifts circadian rhythms in humans according to a phase-response curve (for further references, see Lewy et al. 2004).
We have shown that the timed use of low-dose exogenous melatonin synchronizes the circadian rhythm of body temperature in the elderly (Gubin et al. 2006).
During treatment, the circadian rhythm became similar to that of healthy young adults, except for a lower MESOR; the amplitude increased and the phase variability decreased. Moreover, the age-dependent phase misalignment between body temperature and cardiovascular functions was abolished, and the scattered body temperature phases were re-entrained (Gubin et al. 2013; Gubin et al. 2016a; Gubin et al. 2006). The reason may be a direct, chronobiotic effect of melatonin on the circadian clock as shown by Lewy and colleagues (Lewy et al. 1992; Lewy et al. 2004). In our study, however, an effect via sleep improvement rather than phase-shifting seems more likely. Melatonin induces peripheral vasodilatation leading to a warming of extremities which, in turn, induces sleepiness (Cajochen et al. 2003; Raymann et al. 2005; van Someren 2004). Better sleep has then a direct stabilizing effect on the temperature rhythm, in the sense that it masks it by promoting a more marked and sustained fall (Waterhouse et al. 2001a; Waterhouse et al. 1995).
Melatonin treatment may be beneficial also in patients suffering from diabetes. According to literature data, these patients have a melatonin deficiency and modifications of melatonin receptors, both being risk factors for the development of this disease (McMullan et al. 2013). The strong potential for melatonin use in the treatment of T2DM and other metabolic disorders has been intensely discussed recently (Cardinali, Hardeland 2017; Peschke et al. 2015; Sharma et al. 2015). According to Ramos-Lobo and co-authors, the complementary action of melatonin and insulin may be even more beneficial restoring the normal body temperature rhythm (Ramos-Lobo et al. 2015).
Conclusions. Summarizing, one can conclude that various pathological dysfunctions are associated with cir-cadian disruptions, particularly of the core body temperature rhythm. Though it is not possible to decide to what extent the rhythm changes are caused by the diseases or whether the diseases are caused by circadian disruption. Anyhow, early signs of such disruption can be independent markers for a developing disease. References
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Сведения об авторах
Вайнерт Дитмар, Университет Мартина Лютера, г. Галле, Германия.
Губин Денис Геннадьевич, д. м. н., профессор кафедры
биологии ФГБОУ ВО Тюменский государственный медицинский университет, г. Тюмень; Тюменский кардиологический научный центр, Томский национальный исследовательский медицинский центр РАМН, г. Томск.
Вайнерт Д., Губин Д.Г.
ЦИРКАДИАННЫЙ РИТМ ТЕМПЕРАТУРЫ ТЕЛА: МЕХАНИЗМЫ И МЕДИКО-БИОЛОГИЧЕСКОЕ ЗНАЧЕНИЕ
Цель настоящего обзора состоит в том, чтобы охарактеризовать природу циркадианного ритма температуры человека (зарекомендовавшего себя как маркерный ритм биологических часов), показать его медико-биологическое значение и перспективы клинического использования. Некоторые результаты экспериментов на животных также обсуждаются, поскольку они показывают общие биологические принципы. Аргументируется важность поддержания параметров циркадианного ритма температуры для здоровья и благополучия, а также приведены примеры его изменений в связи с определенными патологиями. Поскольку циркадианный ритм температуры тела имеет особенности на разных стадиях индивидуального развития, рассматриваются его онтогенетические и возрастные изменения, их причины и последствия. Наконец, обсуждаются некоторые способы предотвращения или минимизации последствий нарушений циркадианного ритма температуры.
Ключевые слова: температура, циркадианный ритм, биологические часы, десинхроноз, человек, млекопитающие, здоровье, болезнь, возраст, мелатонин.
