1.1 Introduction

For the past 3–4 billion years, life on Earth evolved under the predictable pattern of solar days; that is, exposure to light during the day and dark at night. Temporal constraints are obvious when considering the “rules of life.” That is, individuals cannot do everything all the time. For instance, energetic requirements are somewhat continuous, whereas energy production or consumption is somewhat sporadic. All organisms partition temporal energetic activities. Indeed, temporal partitioning of photosynthesis, metabolism, gene expression, reproduction, defense, growth, activity, and inactivity is universal among plants and animals. During the evolution of life, organisms internalized the temporal rhythm of Earth’s rotation and eventually developed self-sustaining biological clocks. These internal rhythms with periods of approximately 24 hours are called circadian rhythms, and the structures that generate them are called circadian clocks. A human’s primary circadian biological clock is a paired cluster of about 20,000 nerve cells in the hypothalamus at the base of the brain, called the suprachiasmatic nucleus (SCN). The period of a circadian clock is approximately 24 hours, but daily light exposure sets it to precisely 24 hours. Having our clocks set closer to our environment’s light–dark rhythms optimizes how our bodies function and how we behave.

Circadian clocks are a nearly universal feature of life on this planet, yet over the past century and a half we have managed to manipulate the amount of light in the environment so much that we are disrupting them. As we will learn throughout this book, either too much light exposure at night or too little light exposure during the day can disrupt central and peripheral timing mechanisms, how internal rhythms are entrained to the external environment, and the typical and optimal 24-hour physiological and behavioral functioning of individuals.

1.2 Molecular Mechanisms of the Circadian Clock

At the molecular level, cellular circadian rhythms are formed from interlocking transcriptional–translational feedback loops (TTFL) that drive spontaneous oscillations of gene and protein expression with an approximately 24 hour period. Remarkably, the molecular clock components are expressed rhythmically in nearly every cell of the body and are entrained by signals from the primary clock. The core components of this loop involve the induction of Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) gene expression through E-box enhancers by the transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle arnt-like protein 1 (BMAL1) (Gekakis et al., Reference Gekakis, Staknis, Nguyen, Davis, Wilsbacher, King, Takahashi and Weitz1998; Hogenesch et al., Reference Hogenesch, Gu, Jain and Bradfield1998; Jin et al., Reference Jin, Shearman, Weaver, Zylka, de Vries and Reppert1999). Per and Cry proteins accumulate in the cytoplasm and then form large multimeric complexes which translocate back to the nucleus to interact with CLOCK and BMAL1 and repress their own transcription (Griffin et al., Reference Griffin, Staknis and Weitz1999; Kume et al., Reference Kume, Zylka, Sriram, Shearman, Weaver, Jin, Maywood, Hastings and Reppert1999; Lee et al., Reference Lee, Etchegaray, Cagampang, Loudon and Reppert2001). Progressive degradation of the existing inhibitory complexes then occurs, ultimately leading to renewed transcription of Per and Cry. This feedback loop takes approximately 24 hours to complete a cycle. There are additional feedback loops interlocked with the CLOCK-BMAL1/Per-Cry loop. A prominent loop involves the activation of the retinoic acid receptor-related orphan receptor (ROR) and REV-ERB by the CLOCK-BMAL1 complex which feeds back on BMAL1 to stabilize rhythms (Preitner et al., Reference Preitner, Damiola, Lopez-Molina, Zakany, Duboule, Albrecht and Schibler2002). Deletion of “core clock genes” (or, in some cases, 2+ paralogs of clock genes) reveals their requirement for rhythms in activity (Bunger et al., Reference Bunger, Wilsbacher, Moran, Clendenin, Radcliffe, Hogenesch, Simon, Takahashi and Bradfield2000; Cox & Takahashi, Reference Cox and Takahashi2019; Vitaterna et al., Reference Vitaterna, King, Chang, Kornhauser, Lowrey, McDonald, Dove, Pinto, Turek and Takahashi1994).

1.3 Circadian Rhythms Occur Throughout the Body: Extra-SCN Tissue-Specific Clocks

In addition to the central clock in the SCN, individual organs and cells outside the SCN rhythmically express core clock genes. These are termed peripheral or extra-SCN tissue-specific clocks. Individual cells contain autonomous clocks; importantly, all cells work in concert to time the occurrence of physiological events optimally. The SCN regulates peripheral clocks both through indirect and direct means. Direct regulation of peripheral processes by the SCN are evoked by neural or humoral signaling (e.g., Mohawk et al., Reference Mohawk, Green and Takahashi2012; Ramanathan et al., Reference Ramanathan, Kathale, Liu, Lee, Freeman, Hogenesch, Cao and Liu2018). Indirectly, the SCN regulates the peripheral clocks via neural and humoral signaling factors, as well as by modulating the expression of circadian clock genes. For example, the SCN regulates secretion of hormonal cues that synchronize extra-SCN clocks, such as melatonin and glucocorticoids. Glucocorticoids are hormones released by the adrenal gland, and act via the glucocorticoid receptor in nearly all cells to regulate gene expression. Upon binding the cytosolic glucocorticoid receptor, the ligand-receptor complex enters the nucleus and binds to glucocorticoid response elements on DNA to activate or repress gene expression. Importantly, at baseline there are circadian rhythms in glucocorticoid levels and several circadian genes have glucocorticoid response elements in their regulatory regions (Reddy et al., Reference Reddy, Maywood, Karp, King, Inoue, Gonzalez, Lilley, Kyriacou and Hastings2007). Application of glucocorticoids to isolated cells can induce Per gene expression and thus serves as an important factor for regulating extra-SCN clocks (Balsalobre et al., Reference Balsalobre, Brown, Marcacci, Tronche, Kellendonk, Reichardt, Schutz and Schibler2000; Fonken et al., Reference Fonken, Frank, Kitt, Barrientos, Watkins and Maier2015).

In addition, physiologic cues coordinate or amplify circadian rhythms in extra-SCN cells; these cues include body temperature, feeding, and activity (Schibler et al., Reference Schibler, Gotic, Saini, Gos, Curie, Emmenegger, Sinturel, Gosselin, Gerber, Fleury-Olela, Rando, Demarque and Franken2015). These neural, humoral, and physiologic factors are sensitive to entrainment by the SCN – but they are also regulated by other systemic factors (S. Zhang et al., Reference Zhang, Dai, Wang, Jiang, Hu, Zhang and Zhang2020).

External events, such as food intake (Damiola et al., Reference Damiola, Le Minh, Preitner, Kornmann, Fleury-Olela and Schibler2000) and physical exercise (Ripperger & Schibler, Reference Ripperger and Schibler2001), can indirectly reset peripheral clock rhythms in the liver and elsewhere (Chen et al., Reference Chen, Feng, Zhang, Dong, Wang, Zhang and Liu2019; Landgraf et al., Reference Landgraf, Tsang, Leliavski, Koch, Barclay, Drucker and Oster2015). For example, restricting food intake to certain times of day (time-restricted feeding or TRF) can uncouple the SCN and extra-SCN clocks (Damiola et al., Reference Damiola, Le Minh, Preitner, Kornmann, Fleury-Olela and Schibler2000). Indeed, timing of food intake strongly regulates the liver clock (Hatori et al., Reference Hatori, Vollmers, Zarrinpar, DiTacchio, Bushong, Gill, Leblanc, Chaix, Joens, Fitzpatrick, Ellisman and Panda2012) as well as cardiovascular function (see Chapter 11). Another mechanism of SCN-mediated peripheral clock regulation is by direct modulation of the autonomic nervous system, as described in Section 1.4.

Importantly, synchronizing clock gene expression in these extra-SCN tissues coordinates transcriptional programming of clock-controlled genes (Mavroudis et al., Reference Mavroudis, DuBois, Almon and Jusko2018). This means that myriad cellular functions are governed by the clock in peripheral tissues and also suggests that, during pathology, these intermediary circadian synchronizers may be susceptible to harmful perturbation that could desynchronize circadian oscillators. The remainder of this chapter will introduce circadian regulation of several major body systems; specific chapters in this book will then review clock disruption-elicited pathology in these systems.

1.4 Circadian Regulation of CNS Function

Central nervous system (CNS) function of animals displays distinct and overlapping circadian rhythms (Chapter 6). Indeed examples of circadian fluctuations in learning and memory, sensation and perception, attention, food intake, mating behaviors, maternal behaviors, aggression, drug and alcohol seeking behaviors, as well as regulation of locomotor activity have been reported (Nelson et al., Reference Nelson, Bumgarner, Walker and DeVries2021). These temporal variations are often overlooked and can significantly affect experimental outcomes. In this section we review some common examples of circadian regulation of CNS function. Notably, disrupted circadian rhythms negatively affect CNS function.

1.5 Circadian Regulation of Cardiac Function

Cardiac function is regulated by circadian rhythms (Liu et al., Reference Liu, Walton, DeVries and Nelson2021; Melendez-Fernandez et al., Reference Melendez-Fernandez, Walton, DeVries and Nelson2021; Thosar et al., Reference Thosar, Butler and Shea2018) (Chapter 13). Cardiovascular regulation is associated with sleep–wake patterns (Bastianini et al., Reference Bastianini, Silvani, Berteotti, Martire and Zoccoli2012; Smolensky et al., Reference Smolensky, Hermida, Castriotta and Portaluppi2007) that are linked to underlying circadian rhythms. The circadian regulation of sympathetic and parasympathetic activation modulates heart rate, heart rate variability, blood pressure, vascular tone, and endothelial function (reviewed in Melendez-Fernandez et al., Reference Melendez-Fernandez, Walton, DeVries and Nelson2021). This temporal organization allows the vascular system to produce the necessary factors and mediators, such as prothrombotic and antithrombotic factors, and nitric oxide, at the appropriate time of the day to support activity during the active phase or support recovery and replenishment during the inactive phase. Dysregulation of these circadian fluctuations in cardiac function has been associated with cardiovascular pathology including myocardial infarction, ventricular tachycardia, and sudden cardiac death, which all peak during the early morning (Khan & Ahmad, Reference Khan and Ahmad2003; Manfredini et al., Reference Manfredini, Boari, Salmi, Fabbian, Pala, Tiseo and Portaluppi2013; Muller, Reference Muller1999; Muller et al., Reference Muller, Ludmer, Willich, Tofler, Aylmer, Klangos and Stone1987).

Cells comprising cardiovascular tissue display robust circadian oscillations including vascular smooth muscle, fibroblasts, cardiomyocytes, and cardiac progenitor-like cells, all of which regulate physiological functions including endothelial function, blood pressure, and heart rate (Paschos & FitzGerald, Reference Paschos and FitzGerald2010). Disruption of these rhythms is associated with misalignment of cardiovascular dynamics, including endothelial (Etsuda et al., Reference Etsuda, Takase, Uehata, Kusano, Hamabe, Kuhara, Akima, Matsushima, Arakawa, Satomura, Kurita and Ohsuzu1999), prothrombotic (Takeda et al., Reference Takeda, Maemura, Horie, Oishi, Imai, Harada, Saito, Shiga, Amiya, Manabe, Ishida and Nagai2007), and clotting (Dalby et al., Reference Dalby, Davidson, Burman and Davies2000) factors, which can provoke a pathological response (Rana et al., Reference Rana, Prabhu and Young2020).

Taken together, the available data indicate circadian regulation of the cardiovascular system. Indeed, peripheral clocks and clock genes are expressed in these tissues (Davidson et al., Reference Davidson, London, Block and Menaker2005; Storch et al., Reference Storch, Lipan, Leykin, Viswanathan, Davis, Wong and Weitz2002). Rhythms in vascular function are also observed at the molecular level. RNA sequencing data indicate that 6 percent and 4 percent of protein-coding genes in the heart and aorta, respectively, are transcribed in a circadian fashion (Zhang et al., Reference Zhang, Lahens, Ballance, Hughes and Hogenesch2014). At the cellular level, the core clock genes, including Bmal1, Clock, Per, Cry, and Rev-Erb, serve an important role in maintaining physiological homeostasis of the cardiovascular system. For example, mice with Per2 mutations display reduced nitric oxide production and decreased vasodilatory prostaglandins and elevated vasoconstrictors (Curtis et al., Reference Curtis, Cheng, Kapoor, Reilly, Price and Fitzgerald2007). Cry1/2 deletion leads to salt-sensitive hypertension and increased baroreflex sensitivity in mice (Stow et al., Reference Stow, Richards, Cheng, Lynch, Jeffers, Greenlee, Cain, Wingo and Gumz2012). Given the importance of circadian organization for typical cardiovascular function, the potential of disrupted circadian rhythms for cardiovascular health is dramatic (see Chapter 13).

1.6 Circadian Regulation of Metabolism

Energy acquisition, storage, and utilization are critical for life. Metabolism regulates chemical changes in a cell or organism in order to generate energy or materials needed to grow, reproduce, and function appropriately. The circadian system helps optimize metabolic processes based on distinct metabolic requirements throughout the day to maintain homeostasis. Circadian rhythms in metabolism persist at multiple levels from the function of cellular mitochondria, to hormonal release, to behavioral rhythms in food intake.

Humans and other organisms face distinct metabolic demands based on time of day. A critical aspect of this is that daily behavior is partitioned into an active (wakefulness) and rest (sleep) phase. For understandable reasons, the majority of food intake occurs during an animals active phase, with circadian fluctuations in hunger and appetite contributing to this time of day difference in feeding (Scheer et al., Reference Scheer, Morris and Shea2013). There are also differences in cravings for specific foods based on time of day, with an increased preference for higher caloric foods as the onset of the sleep phase approaches (Scheer et al., Reference Scheer, Morris and Shea2013). This is thought to contribute to the increased risk for obesity and metabolic disorders that occurs in night shift workers – night shift workers are awake and active at a time where their bodies are primed for higher calorie food intake (Bouillon-Minois et al., Reference Bouillon-Minois, Thivel, Croizier, Ajebo, Cambier, Boudet, Adeyemi, Ugbolue, Bagheri, Vallet, Schmidt, Trousselard and Dutheil2022).

Importantly, metabolic regulation is not simply an output of the circadian system. Food intake feeds back on the clock to reinforce rhythms and to adapt physiology to tissue-specific needs. Along with changes in food intake, there are also time-of-day differences in whole body energy expenditure: metabolic rate is reduced during sleep compared to wakefulness (Fraser et al., Reference Fraser, Trinder, Colrain and Montgomery1989). Increases in energy expenditure occur during sleep restriction (although increases in energy expenditure are often countered by increased food intake) (Markwald et al., Reference Markwald, Melanson, Smith, Higgins, Perreault, Eckel and Wright2013; McHill et al., Reference McHill, Melanson, Higgins, Connick, Moehlman, Stothard and Wright2014). However, when humans are sleep restricted and maintained on bed rest, energy expenditure during the typical sleep phase is still lower than during the early active phase (Jung et al., Reference Jung, Melanson, Frydendall, Perreault, Eckel and Wright2011), suggesting the presence of an underlying endogenous rhythm.

Because of the differences in energy intake and expenditure that occur with predictable daily rhythm, there are also rhythms in the underlying hormonal and cellular processes associated with metabolism. Regulation of key metabolic hormones varies throughout the day both due to circadian regulation and as a direct consequence of timing of food intake. For example, because food intake occurs primarily during the active phase, there are increases in most intermediary metabolites including glucose, amino acids, and lipids in the blood during the active phase (reviewed in Reinke & Asher, Reference Reinke and Asher2019). The circadian clock, however, is critical for buffering against excessive fluctuations in metabolic factors. For example, blood glucose is regulated by the circadian system; glucose transporters oscillate in a circadian manner, presumably in anticipation of relative nutrient abundance during the active compared to the inactive phase (Reinke & Asher, Reference Reinke and Asher2019). Circadian function in key tissues and cells that mediate blood glucose are critical. Indeed, disrupting clock function in the liver and pancreas impacts glucose regulation (Lamia et al., Reference Lamia, Storch and Weitz2008; Marcheva et al., Reference Marcheva, Ramsey, Buhr, Kobayashi, Su, Ko, Ivanova, Omura, Mo, Vitaterna, Lopez, Philipson, Bradfield, Crosby, JeBailey, Wang, Takahashi and Bass2010).

Given this tight regulation between the circadian system and metabolism, it follows that disruption of the circadian clock by genetic or environmental means results in metabolic disruption. Susceptibility to diet-induced obesity in a genetic circadian model was first shown in clock mutant mice (Turek et al., Reference Turek, Joshu, Kohsaka, Lin, Ivanova, McDearmon, Laposky, Losee-Olson, Easton, Jensen, Eckel, Takahashi and Bass2005). Subsequently, mutations in many clock linked genes have been associated with metabolic dysfunction (see table 2 in Fonken & Nelson, Reference Fonken and Nelson2014). Environmental circadian disruption in rodent models, including exposure to light at night (Fonken, Aubrecht, et al., Reference Fonken, Aubrecht, Melendez-Fernandez, Weil and Nelson2013; Fonken et al., Reference Fonken, Workman, Walton, Weil, Morris, Haim and Nelson2010; Fonken & Nelson, Reference Fonken and Nelson2013; Fonken, Weil, et al., Reference Fonken, Aubrecht, Melendez-Fernandez, Weil and Nelson2013), constant light (Coomans et al., Reference Coomans, van den Berg, Houben, van Klinken, van den Berg, Pronk, Havekes, Romijn, van Dijk, Biermasz and Meijer2013; Fonken et al., Reference Fonken, Workman, Walton, Weil, Morris, Haim and Nelson2010), simulated shift-work protocols (Barclay et al., Reference Barclay, Husse, Bode, Naujokat, Meyer-Kovac, Schmid, Lehnert and Oster2012; Salgado-Delgado et al., Reference Salgado-Delgado, Saderi, Basualdo Mdel, Guerrero-Vargas, Escobar and Buijs2013), and non-24 hour light cycles (Karatsoreos et al., Reference Karatsoreos, Bhagat, Bloss, Morrison and McEwen2011), are also associated with metabolic dysfunction. Furthermore, humans that are at risk for circadian disruption by engaging in activities such as shift work are at increased risk for developing metabolic syndrome (Pietroiusti et al., Reference Pietroiusti, Neri, Somma, Coppeta, Iavicoli, Bergamaschi and Magrini2010). Perhaps not coincidental, the global obesity epidemic parallels rapid increases in disruptive nighttime light exposure in recent decades. This work is reviewed in Chapter 10. Overall, metabolism and the circadian system are integrally associated.

1.7 Circadian Regulation of Immune Function

The diverse activities in which humans and other animals engage throughout the day come with different risks for encountering pathogens, toxins, and injuries. This suggests that coordinating responses to such threats would also be adaptive, with the immune system representing a major responder. Under healthy conditions, the immune systems may promote a state of anticipation and enhanced vigilance prior to the onset of the active phase, and repair and rejuvenation at the end of the active phase (Curtis et al., Reference Curtis, Bellet, Sassone-Corsi and O’Neill2014).

The immune system differentially responds to challenges based on time of day (Haspel et al., Reference Haspel, Anafi, Brown, Cermakian, Depner, Desplats, Gelman, Haack, Jelic, Kim, Laposky, Lee, Mongodin, Prather, Prendergast, Reardon, Shaw, Sengupta, Szentirmai and Solt2020). For example, exposure to the same E. coli endotoxin challenge during the active versus inactive phase produces striking differences in mortality: rats that receive E. coli endotoxin during their inactive phase exhibit approximately 10 percent mortality versus approximately 80 percent mortality to the exact same dose during the active phase (Halberg et al., Reference Halberg, Johnson, Brown and Bittner1960). Similarly, humans with rheumatoid arthritis show increased pain and inflammatory markers during the nighttime (rest phase) and early morning (Gibbs & Ray, Reference Gibbs and Ray2013; Ingpen, Reference Ingpen1968; Perry et al., Reference Perry, Kirwan, Jessop and Hunt2009). These changes in immune function are associated with direct circadian regulation of immune cells as well as due to circadian regulation of hormones that gate immune responses (e.g., glucocorticoids).

Recent work has illuminated how the circadian system drives healthy daily rhythms in immune responsivity and migration. Every immune cell examined expresses the circadian clockwork necessary for approximately 24 hour rhythms entrained by intermediary oscillators, and these clock genes refine expression of immune-related genes. In mouse macrophages, the clock gene Rev-erba (e.g., Nr1d1) peaks around Zeitgeber time (ZT) 12 (late inactive phase, where ZT represents 24 hours of the day with ZT0 = lights on) (Alexander et al., Reference Alexander, Liou, Knudsen, Starost, Xu, Hyde, Liu, Jacobi, Liao and Lee2020; Gibbs et al., Reference Gibbs, Blaikley, Beesley, Matthews, Simpson, Boyce, Farrow, Else, Singh, Ray and Loudon2012); this transcriptional repressor inhibits expression of the core clock gene Bmal1, while also repressing expression of inflammatory genes. At the nadir of Rev-erb expression – during the active phase – genes with REV-ERB regulatory binding sites are derepressed and are present at higher levels. Thus, REV-ERB provides an example of how a clock-related gene can drive daily oscillations in the functional outputs of immune cells.

Similar daily patterns in expression and reactivity are observed for other clock genes and cell types, respectively. Interestingly, there are also rhythms in immune cell release into blood and extravasation into inflamed tissue: most subsets show highest release and migration in mice during the inactive phase, and Bmal1 deletion in either endothelial cells or leukocyte subsets ablate these migratory rhythms (He et al., Reference He, Holtkamp, Hergenhan, Kraus, de Juan, Weber, Bradfield, Grenier, Pelletier, Druzd, Chen, Ince, Bierschenk, Pick, Sperandio, Aurrand-Lions and Scheiermann2018). The existence of this intrinsic daily rhythm in immunity suggests it may have an adaptive benefit for optimally balancing preparation of immunity for experiencing infection or injury during active phases versus undergoing rejuvenation or repair during rest (Westwood et al., Reference Westwood, O’Donnell, de Bekker, Lively, Zuk and Reece2019).

1.8 How Do We Disrupt the Clock?

As noted, circadian rhythms can be entrained by several external cues, primarily light exposure and food intake; thus, disrupting these entraining cues can perturb circadian regulation of physiology and behavior (Vetter, Reference Vetter2020).

1.8.1 Environmental Lighting

As mentioned, life evolved on Earth with an internal timing system aligned with bright days and dark nights. The invention of electric lighting approximately 150 years ago initiated social and economic revolutions, but also effectively ended completely dark nights (Figure 1.1). Artificial light currently floods the skies with a night glow known as “light pollution.” Light pollution is defined as the alteration of natural night light caused by anthropogenic sources of light (Falchi et al., Reference Falchi, Cinzano, Duriscoe, Kyba, Elvidge, Baugh, Portnov, Rybnikova and Furgoni2016). According to Falchi et al., 80 percent of the world and over 99 percent of Europe and the United States live under polluted night skies. Sources of outdoor artificial light include vehicles, buildings, street and traffic lights, and signs. Of course, light has also been brought indoors; sources of indoor artificial light includes light bulbs, TVs, computer screens, e-books, tablets, phones, and other electronic devices. Incandescent light bulbs initially emitted light of a full spectral composition. Technological advances and ecological concerns have driven the development of more cost- and energy-efficient sources of light, viz., light-emitting diodes (LEDs). The spectral composition of LED lights negatively affect the environment (Gaston et al., Reference Gaston, Visser and Holker2015), as well as circadian rhythms. LEDs emit light spectra with a short-wavelength peak, that, as previously described, coincides with the maximal sensitivity of melanopsin, the primary photopigment that conveys environmental light information to the SCN to entrain circadian rhythms. Activation of this pathway during the evening or night may disrupt the internal cycle of clock gene expression/interactions, reset the circadian clock(s), and lead to disrupted circadian rhythms in humans (Brown et al., Reference Brown, Brainard, Cajochen, Czeisler, Hanifin, Lockley, Lucas, Munch, O’Hagan, Peirson, Price, Roenneberg, Schlangen, Skene, Spitschan, Vetter, Zee and Wright2022) as well as other animals exposed to anthropogenic light pollution (see Chapter 15).

Figure 1.1 Satellite image illustrating nighttime skyglow across the globe.

Credit: NASA Earth Observatory images by Joshua Stevens, using Suomi NPP VIRS data from Miguel Roman, NASA’s Goddard Space Flight Center.

1.9 Conclusions

Billions of years of daily light–dark cycles led to the evolution and refinement of the circadian system. In mammals, the primary pacemakers are the SCN, which help entrain peripheral clocks via secreted cues and direct nervous system input. These cues, in combination with extra-SCN signals, control the timing of molecular clocks in nearly every cell of the body. Molecular clocks also regulate cell-specific processes, leading to circadian regulation of nearly every bodily function – here, we introduced how the circadian system regulates homeostasis throughout the body by regulating the function of major body systems including the CNS, metabolism, the cardiovascular system, and immunity. Circadian regulation of physiology is adaptive, as it optimizes body functions for predictable daily activities during active–inactive cycles. Unfortunately, circadian function in humans and other animals are disrupted by technologies developed over the past 150 years, such as artificial light at night. Overall, the circadian system is an extraordinary and evolutionarily conserved feature of animals on Earth that helps optimize physiology and biological output for the time-of-day. Future research will further explore how the circadian system is interwoven with nearly every bodily system and how this ubiquitous system can be manipulated to improve health and survival of life on Earth.