Introductory Chapter: Untangling the Essential Links among the Circadian Rhythm, Homeostasis of the Human Body, and the Nutritional, Behavioural, and Pathological Interferences

1. Introduction

The vast majority of living entities are subject to unavoidable and predictable conditions of 24-hour changes in their environment, having the ability to adjust to the day-night cycle. To manage these daily changes in periods of light and darkness, almost every living organism has developed an internal system of synchronisation or circadian clock. This tremendous discovery dates back to the beginning of the eighteenth century when Jean-Jacques d’Ortous de Mairan performed the first chronobiology experiment on Mimosa pudica, a plant that visibly responds to circadian changes [1, 2].

2. Circadian, infradian, and ultradian rhythms

Each living organism carries out its activity for approximately 24 hours by:

• obtaining energy (nutrients);

• optimising energy consumption by using it for daily activities and storing the rest for future needs;

• protection from predators;

• regeneration or growth processes;

• reproduction.

All these functions are channelled by a circadian rhythm, which adjusts the body’s ability to perform the demanded tasks by assigning each role at an appropriate time of day or night. Even isolated from solar triggers, the biological clock keeps unaltered its endogenous period of about 24 hours under constant conditions. In actual life, circadian clocks are permanently entrained by external signals, the most significant being light, which also directs the daily rhythmicity of all other environmental cues.

Furthermore, bearing the utmost importance for humans, biological timing is essential for coordinating homeostasis, physiological processes, from gene expression to drug metabolism, and behaviour, in the same way as the disruption of biological synchronising mechanisms are evoked in significant pathological surges. The temporal information is mainly driven by the Earth’s rotational cycle of 24 hours, imposing an equivalent rhythmic profile in almost every living entity, as profoundly engaged as the molecular level should be considered [1, 2].

In addition to circadian rhythms, the periodicity of certain events is described in more extended time frames, called generically infradian rhythms, which can last from several days, as is the case of the menstrual cycle, to annual cycles mainly found in animals that display infradian patterns in reproduction, hibernation or seasonal migration. Contrary-wise, the biological paces with a period shorter than 24 hours, starting from seconds or minutes to a few hours, are called ultradian rhythms. One of the most accurately described and studied ultradian rhythms is the 40 minutes cycle of cellular respiration displayed by Saccharomyces cerevisiae in aerobic culture conditions. Besides that, an interesting and early revealed human ultradian rhythm is the REM-NREM sleep sequence with an extent of 90 minutes and an occurrence of 3–5 cycles during normal sleep, also reflected on the recurrent functional pattern of muscles tone, brain electrical and oculomotor activity and nevertheless of energy utilisation. These rhythms are ubiquitously expressed in all biological systems and established in all organisms, from unicellular ones to mammals, from single cells to complex biological mechanisms.

3. The three time-setting entities: circadian endogenous clock—the solar clock—the social clock

The rhythms of all organisms are self-sustained, they synchronise with the environment, are subjected to permanent entrainment, but are driven endogenously. The human organism is nowadays considered to be at the crossroads of three different timers: the circadian endogenous clock—the solar clock—the social clock [3, 4].

The circadian clock is a highly convoluted and outstandingly designed network of regulators that interplay throughout 24-hour periods to generate, sustain and synchronise the circadian pattern. This hierarchical biological setup has in its core the central clock that identifies a series of input signals from the environment, having the unique feature of perpetual entrainment, output pathways that interconnect with the endocrine system and the autonomic nervous system, and the most profoundly expressed and intimately embodied circadian machinery, the molecular clock present in every cell. Through a plethora of genes, transcriptional factors, and proteins, this molecular clock undergoes a series of modulations at the level of mRNA and proteins by regulatory transcriptional-translational feedback loops, driven in a tissue-specific manner with the outcome of physiological homeostasis [5, 6].

The solar clock emerges from the Earth’s daily rotation, as its surface is sequentially exposed to and respectively deprived of light, basically a geophysical light-dark timetable set by the Sun.

The social clock refers to local time, as it is displayed on a watch and is derived from a combination of solar time and societal responsibilities. Mainly arousing at the age of educational integration of the individual in a strict schedule institution, as it is the case of schools and universities, but also comprising elements regarding feeding times, television and internet spending time, video games for teens, social gatherings with family and friends, the social regulatory pattern is of paramount prominence in understanding the new circadian pattern of modern human organisms [7, 8, 9].

4. The circadian topology of humans

The interplay between these three time-setting foundations concealed under a veil of secrecy governs the individual physiologic and behavioural patterns of humankind. As the embodiment of this time-regulatory trinity, humans belong to different chronotypes, depending on their genetic clock mechanisms, as well as their living environment, sex, and age. The circadian topology of humans is mainly depicted by three different characters, the early risers or the morning chronotype, the late risers that express an evening chronotype, and an intermediate or neither type that has rather oscillatory outlines. These typologies are reported to be modulated during the life course, the evening type having a predilection in adolescence and in young adults, a fact that is dramatically changed in later developmental stages, the morning type overlapping to physiological ageing. In addition, gender is quite important in portraying the chronotype, as men are usually reported as being mostly late riser chronotypes. As the rhythmic functioning of the organism is scientifically reasoned, the prevalence of many diseases was causatively linked with circadian disruption. We are nowadays witnessing a tremendous incidence of metabolic disorders, essentially obesity and diabetes, cardiovascular disorders in their outstanding diversity, neurodegenerative impediments, psychiatric imbalances, major sleep conditions, and even cancer and immune system diseases, which are all originating primarily in the misalignment of the inner biochemical circadian state of an individual with the outer environmental liabilities [8, 9, 10, 11, 12, 13, 14, 15, 16, 17].

Considering the circadian phenotype, the interindividual differences should be carefully considered when administering drugs, with the particular purpose of augmenting the therapeutic effect and reducing their side effects, in agreement with the 24 hour driven hormones synthesis, blood pressure, body temperature, heart and respiratory rates, central nervous system activity. Clinical chronobiology is a new emerging realm that merges chronopharmacology and chronotherapeutics as areas of medical and pharmaceutical interest, adjusting the treatment time per chronopharmacokinetics and chronopharmacodynamics parameters and the circadian biological unique pattern displayed by a certain patient [18, 19, 20, 21].

5. The hierarchical organisation of the human circadian system

In mammals, the central clock, also called pacemaker, that essentially orchestrates the circadian behaviour, resides in the suprachiasmatic nucleus (SCN), located near optic nerves. Even though many theories were issued regarding the mechanisms behind the mammalian circadian clock, today it is generally accepted that after light perception, the SCN sends regulatory outputs toward subsequent CNS levels, and in a cascade of immediate events, it regulates the clock genes expressed in periphery, coordinating the local physiological milieu by rhythmically triggering tissue-specific transcriptional pathways. The hierarchical organisation of this system endorses an orchestrated control imprinted by the central pacemaker, which simultaneously perceives information from the exogenous stimuli and communicates the processed data to downstream effector networks as accurately as cellular mechanisms are envisioned to align the physiological characteristics to the circadian pattern. The endogenous circadian machinery is self-sustained, independent of the presence of external inputs, but in the meantime permanently subjected to alignments by their occurrence, initiating a so-called “photoentrained system” [22, 23, 24].

The day-night phase alternation ignites a congregation of signals, mainly light, but also temperature or feeding triggers, which can act as prompts, called zeitgebers, meant to synchronise endogenous circadian systems. Fundamentally, the circadian clock is entrained by direct retinal innervation. Light is detected exclusively by the eyes, by a particular arrangement of specific cells and the retinal photopigment, melanopsin. This photic information is conducted by photosensitive ganglion cells expressed at the retina level through the retinohypothalamic tract, directly to the pacemaker, acquiring the entrainment and alignment with the solar clock. Through its rhythmic outputs, the SCN harmonises all the cellular circadian clocks present in every cell of the body organs and tissues to adapt their physiologic features to the external circadian signals [25].

The molecular circadian clock consists briefly of auto-regulated transcriptional and translational feedback loops that are impressed by the oscillatory gene expression controlled by their protein products. The gene expression profiling is under the direct control of the circadian transcriptome, aligning this pattern with the one present in the SCN and peripheral tissues. Circadian transcriptional fluctuations are mandatory for the connected metabolic and functional interplay among various levels of organisation inside a cell, in a particular tissue, and throughout the entire body for the individual roles to be integrated into the complex biological universe of the human organism. A single conductor orchestrates the circadian equilibrium, but every cell has a clear view of the data received from it, not allowing any desynchronisation, nor interferences, in a healthy entity [24, 26].

Several mechanisms may contribute to the complex circadian tissue reprogramming in close relationship with the modulation of the transcription process. The first one is presumably established by epigenetic frames having echoes in the DNA structure that undergoes serious chemical modifications simultaneously with histone proteins. All these amendments command, in their turn, the specific binding of transcription factors to regulatory regions upon the genes, remodelling the transcriptional scenery according to the circadian pattern. The clock genes imprint circadian fluctuations at the epigenome level, correlated with the rhythms exhibited by the transcriptome. The tissue-specific epigenetic arrangements are crucial for setting up cellular identity. In addition, another essential feature regards the interactions established between circadian regulatory proteins and transcriptional factors with characteristic individual profiling, a supplementary regulatory pathway after gene expression regulatory transactions. In line with the previous remarks, the transcriptional expression of regulatory RNA fragments also illustrates a rhythmic profile. Emphasising the cellular machinery synchronisation, the complementary transcriptome regulation through systemic signalling is conducted directly from the SCN or indirectly by the central pacemaker output signals [27, 28].

The SCN is also sensitive to other non-photic inputs from adjacent cerebral regions or the environment, mainly feeding and temperature cues. The feeding time has intense rhythmic reverberations at the level of hepatic transcriptome and the 24-hour body temperature cyclic pattern adjusts the eventually occurring misalignments of the peripheral clock conveyed by various tissues.

Consistent with these clarifications, it should be acknowledged that the health state of an organism is highly dependent on the interplay between circadian molecular and systemic mechanisms, and the extent of its implementation at the peripheral transcriptional level. The most abrupt discrepancies are registered by humans who experience jet lag when travelling between different time zones or the more prevalent case of shift workers. The latter endangers their circadian synchronisation pattern by having a permanently dysregulated light-dark routine and a misaligned feeding schedule. All these aspects are triggering unusual signalling pathways to the inner pacemaker. Consequently, the solar clock and the biological one is completely out of phase, resulting in a disequilibrium generally accredited with the designation “internal desynchronisation” [29, 30, 31, 32].

This disturbed state is associated with malfunctioning in transcriptional processes, altered peripheral tissue sensitivity by corrupted input-output transitions, mainly transcribed to chronic disorders located in the most vulnerable territories of the body [33].

To a more profound analysis, the transcriptome disruptions are also of great interest for drugs metabolism, as the cytochrome P450 isoforms and several other enzymes that are relevant for the biologic transformations conducting to toxic metabolites or an amplified structural alteration of the therapeutically active molecules are synthesised based on rhythmically expressed genes. This advances a relevant concern upon the efficacy-toxicity balance of a therapeutic molecule or a xenobiotic, based on its chronopharmacokinetic profile, raising a genuine concern on the time of administration and the specific circadian pattern of a patient (Figure 1), which should be considered when special treatment schemes are applied, mainly comprising chemotherapy, cardiovascular and endocrine targeting drugs [34, 35, 36].

Figure 1.

Global view upon the human circadian clock.

A significant limitation in designing personalised time-targeted therapies is the absence of relevant biomarkers able to replicate with fidelity the individual circadian features in the highly variable human population. Even though the assessment of a series of hormones levels, namely melatonin, cortisol, DHEA or the body temperature, on a 24-hour basis, can presume roughly the circadian outlines, or that a few transcriptomic and metabolic data can be corroborated and statistically inferred to give a more accurate image of this unique array, no readily available and perfectly concluding techniques can be applied for comprehending the degree of internal desynchronisation. A more desired and attainable perspective would be the actual restoration of the inner state of synchrony by using gradually employed procedures, transcriptomic and environmental triggers to reset timers profoundly endorsed at the molecular level. The outcome should immediately be visible in physiologic sleep-wake cycles, with normally displayed temporal behaviour and the general health state reestablished or at least partially recuperated [37, 38, 39].

The circadian machinery is organised in a hierarchy of multiple oscillators, the suprachiasmatic nucleus (SCN) being the central pacemaker at the top of the pyramid. It is synchronised by the 24-hour cycle external signals (the primary input is light and other secondary cues as temperature and feeding), and sequentially, it coordinates the physiological outputs. The multi-oscillator network is synchronised through multiple lines of communication. Peripheral oscillators, present in everybody cell, are reset by timing cues from the SCN, which regulate local circadian physiology. The molecular clock comprises several interconnected transcription feedback loops. The intercellular synchronisation within the SCN is essential for the optimum functioning of the entire body clock.