Circadian clock: The master clock regulating aging, disease, and bodily activities

Highlights:

• The circadian rhythm controls the daily cycle and activities of various organs
• Disruption of the circadian clock has been associated with diseases
• The circadian clock is implicated in the aging process
• Genes, lifestyle, and nutrition influence the circadian clock

Introduction

The circadian rhythm is the 24-hour cycle in which the brain regulates states of alertness and sleepiness by responding to light changes in the surrounding environment. The name is derived from 2 words, circa meaning around and dies meaning day. During the process, various physical, mental, and behavioral changes occur to help the body adapt to a particular part of the cycle. The circadian pacemaker is located in the suprachiasmatic nuclei within the anterior hypothalamus. This pacemaker regulates circadian rhythms of various physiological processes like sleep/wake cycles, blood pressure, body temperature, cell division, bodily secretions and hormones, and others. Additionally, this pacemaker controls the peripheral clocks through a complex network of neural projections and humoral signals. 

Regulation of the circadian rhythm

The role of suprachiasmatic nuclei (SCN) in circadian regulation was discovered in the 1970s during experiments carried out on rats (1). In these trials, SCN in these rats were lesioned, leading to disruptions in endocrine and behavioral rhythms (1). Additionally, transplanting SCN to these animals led to restoring some of the lost functionality. Moreover, research has highlighted that disrupting rhythmicity in hamsters led to reduced longevity and that transplanting SCN restored the rhythmic functionality and extended life (2).  

The SCN, also known as the central clock, exert their effect as the master regulators of the circadian rhythm through neural projections that extend to regions of the thalamus, hypothalamus, and limbic system (3, 4). One of the main organs targeted by the SCN is the pineal gland (1, 3). The latter is a structure located in the brain and is responsible for producing a hormone called melatonin (3). Melatonin production is rhythmic and is characterized by low levels during daytime and high levels after sunset, with the peak being between 11 AM and 3 AM (3).     

In addition to SCN, a compelling body of evidence suggests the presence of peripheral regulators of circadian rhythms located in various organs (1, 3). The effect of these peripheral circadian regulators has been observed in isolated organs like lungs, livers, and tissues grown in culture dishes (1, 5). This highlights that both central and peripheral components regulate the circadian rhythm through a dual feedback loop.

In addition to the above, the regulation of circadian rhythm has been found to have a genetic component as well (1). This became evident with the discovery of the Clock gene in mice in 1994. According to literature, mutations in this gene lead to disturbance of the circadian rhythm; however, its removal did not prompt significant disruption in the rhythm due to the presence of other genetic regulators (6). Ever since the discovery of the Clock gene, scientists have discovered several other genes with implications on the circadian clock, such as genes coding brain and muscle ARNT-like protein (BMAL1) and albumin D-binding protein (DBP), among others (1, 6). 

Circadian clock and body systems

The circadian system has been found to influence the body’s overall physiology and affect both disease and health states. For example, the research highlighted that disruption of the circadian rhythm is associated with increased susceptibility to infectious agents, metabolic syndromes, sleep disorders, aging, mental conditions, and even cancer (7). Additionally, disturbance in the genetics related to the circadian rhythm has been found to influence several disease states.

In the case of sleeping disorders, research has pointed out that mutation in the circadian clock gene Cryptochrome 1 (CRY1) is associated with a condition known as delayed sleep phase disorder (DSPD). The latter is a form of insomnia characterized by a persistent delay in falling asleep to unusually late times (7, 8). People affected by the condition are often referred to as “night owls”. With these mutations, the new CRY1 variant prolongs the circadian molecular rhythm period and reduces the expression of circadian activator proteins like Clock and BMAL1 (8). The prevalence of DSPD can reach up to 10%. In contrast, familial advanced sleep phase disorder (FASPD) is a circadian condition characterized by habitual sleep times that are earlier than usual and attributed to genetic components (8).

In addition to the above, research has highlighted that the circadian clock also regulates the immune response to extracellular pathogens (9). This regulation is attributed to the effect of the circadian clock that extends from activation of innate and adaptive immunity to host-pathogen interactions (7). Additionally, research has highlighted that the time of the day in which infection occurs plays a major role in how the disease progresses (9). In a trial by Edgar et al., mice inoculated intranasally with the herpes virus during the onset of the resting phase of the daily cycle had a 10-fold higher viral replication compared to mice infected before the active part of the day (9). T and B lymphocytes have also been found to exhibit circadian patterns, where their numbers were observed to peak during the resting phase of the organism (7). In addition to regulating the response to external pathogens, disruptions in elements of the circadian clock also contribute to the incidence of autoimmune disorders (7). In a trial by Sutton et al., loss of the BMAL1 molecular clock component in an experimental multiple sclerosis model led to an increase in pathogenic T lymphocytes in the central nervous system, contributing to neuroinflammation and demyelination (10).

The role of the circadian clock in metabolic function is evident, in which changes or disruptions in the daily activity-rest rhythms and subsequent feeding patterns have been associated with metabolic syndrome (7). According to research, the circadian clock controls metabolism by influencing transcriptional metabolic pathways (7). For example, CRY1 suppresses hepatic gluconeogenesis during fasting through regulating cyclic adenosine monophosphate and cyclic adenosine monophosphate response element binding protein (CREB) in addition to other pathways. A trial by Guan et al. on mice explored another pathway and found that diet-induced obesity triggered sterol regulatory-element binding proteins (SREBPs) expression in the liver, leading to fatty acid synthesis and oxidation (11). SREBPs are transcription factors that are involved in lipid homeostasis, which if disturbed, could lead to metabolic consequences.

In addition to the above, research has connected disturbance of the circadian rhythm with increased cancer susceptibility in various body organs and systems (7). Evidence from multiple studies has attributed this disturbance to mutations and changes in the circadian genes (7, 12). For example, mutations in circadian clock regulating Period genes Per1, Per2, and Per3 have been linked to cancers like acute myeloid leukemia, chronic myeloid leukemia, and colorectal carcinoma (12). These cancers have been attributed to changes in cellular functions such as cell cycle control, chromatin remodeling, and DNA damage repair. In a study by Sulli et al., targeting of nuclear receptors REV-ERBs by experimental medications selectively targeted cancer cells and oncogene-induced senescent cells without affecting the viability of normal cells (13). These experimental agents played a role in regulating de novo lipogenesis and autophagy, two of the cancer hallmarks, through activation of apoptosis in cancerous cells. REV-ERBs are nuclear hormone receptors that represent an essential component of the circadian clock and are considered as master regulators of rhythmicity (14). 

Recent research has highlighted a link between disturbance in circadian clock and sarcopenia (15). The latter is a condition characterized by involuntary loss of skeletal muscle mass function due to aging (15). This circadian-induced sarcopenia is attributed to disturbances in the molecular circadian clock and mitochondrial functionality. 

Circadian clock and aging

The connection between circadian rhythm and the aging process has been established. According to research, aging contributes to a decline in neuronal activity rhythms in the SCN (7). Additionally, available evidence has demonstrated that disruption of the BMAL1 in mice has led to premature aging and reduced lifespan (16).

Recent research in aged stem cells has revealed that contrary to what is expected, aging does not offset circadian rhythmicity but rather rewires the circadian transcriptional profiles (17). In other words, the aged stem cells retain their rhythmic behavior. However, transcription is rewired in a way that switches from expression of genes involved in homeostasis to those involved in stress response, inflammation, DNA damage, and inefficient autophagy. This highlights that the circadian clock redirects the cells into a new rhythmic function with aging (7). It is important to note that the molecular pathways involved in this process are not fully understood and remain under investigation. 

Additional research on aging and circadian regulation has revealed the influence of the circadian clock on the metabolic regulation of polyamine (7). The latter has multiple modulatory actions on cells, and alteration in metabolism of polyamines in a way leading to a reduction in their levels has been linked to aging. In an experiment by Zwighaft et al. on mice, polyamine levels were found to be influenced by the circadian clock, and in turn, polyamines were found to regulate the circadian period (18). In their study, the investigators highlighted that mutations in Per1 and Per2 led to negligible oscillation in expression levels of Odc, Srm, and Amd1. The latter are enzymes involved in the biosynthesis of polyamines, which again are known to influence the aging process. The authors also revealed that the effect of longer circadian periods could be reversed with supplementation of polyamines in diet (18). The researchers concluded that the link between polyamine synthesis and circadian clocks represents a potential age-slowing target that could be influenced by nutritional intervention, prompting further research into the process.

According to literature, sodium, potassium, and calcium ion channels are implicated in the rhythmic process modulation (19, 20). This prompted researchers to explore the relation between SCN ion channel deterioration and the aging process (19). Results from a study by Farajnia et al. conducted on mice found that age influences the electrical rhythm of SCN, highlighting the impact of aging on the circadian clock (19).

Conclusions

The circadian clock is the master regulator of the body's various day and night activities. Research has highlighted that in addition to SCN, circadian rhythms are also controlled by genetic and peripheral components. In humans, the circadian rhythm can be influenced by lifestyle, hereditary, and seasonal factors (21). Simple interventions that influence the circadian rhythm have been found to have a significant impact. For example, having a fixed feeding-fasting cycle has been shown to prevent or reverse chronic illnesses in experimental models. In humans, research has been demonstrated that erratic eating behavior is associated with diseases and that fixing the nutritional cycles confer better protection from conditions such as breast cancer (22).

References 

1.            Vitaterna MH, Takahashi JS, Turek FW. Overview of circadian rhythms. Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism. 2001;25(2):85-93.

2.            Hurd MW, Ralph MR. The significance of circadian organization for longevity in the golden hamster. J Biol Rhythms. 1998;13(5):430-6.

3.            Hofstra WA, de Weerd AW. How to assess circadian rhythm in humans: A review of literature. Epilepsy & Behavior. 2008;13(3):438-44.

4.            Buijs RM, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci. 2001;2(7):521-6.

5.            Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000;288(5466):682-5.

6.            Buhr ED, Takahashi JS. Molecular components of the Mammalian circadian clock. Handbook of experimental pharmacology. 2013(217):3-27.

7.            Rijo-Ferreira F, Takahashi JS. Genomics of circadian rhythms in health and disease. Genome medicine. 2019;11(1):82-.

8.            Patke A, Murphy PJ, Onat OE, Krieger AC, Özçelik T, Campbell SS, et al. Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. Cell. 2017;169(2):203-15.e13.

9.            Edgar RS, Stangherlin A, Nagy AD, Nicoll MP, Efstathiou S, O'Neill JS, et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(36):10085-90.

10.          Sutton CE, Finlay CM, Raverdeau M, Early JO, DeCourcey J, Zaslona Z, et al. Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease. Nat Commun. 2017;8(1):1923.

11.          Guan D, Xiong Y, Borck PC, Jang C, Doulias P-T, Papazyan R, et al. Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes. Cell. 2018;174(4):831-42.e12.

12.          Fu L, Kettner NM. The circadian clock in cancer development and therapy. Progress in molecular biology and translational science. 2013;119:221-82.

13.          Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 2018;553(7688):351-5.

14.          Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature. 2012;485(7396):123-7.

15.          Choi Y, Cho J, No M-H, Heo J-W, Cho E-J, Chang E, et al. Re-Setting the Circadian Clock Using Exercise against Sarcopenia. International journal of molecular sciences. 2020;21(9):3106.

16.          Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes & development. 2006;20(14):1868-73.

17.          Solanas G, Peixoto FO, Perdiguero E, Jardí M, Ruiz-Bonilla V, Datta D, et al. Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress. Cell. 2017;170(4):678-92.e20.

18.          Zwighaft Z, Aviram R, Shalev M, Rousso-Noori L, Kraut-Cohen J, Golik M, et al. Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age. Cell Metab. 2015;22(5):874-85.

19.          Farajnia S, Meijer JH, Michel S. Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons. Neurobiology of Aging. 2015;36(6):2176-83.

20.          Harvey JRM, Plante AE, Meredith AL. Ion Channels Controlling Circadian Rhythms in Suprachiasmatic Nucleus Excitability. Physiological Reviews. 2020;100(4):1415-54.

21.          Farhud D, Aryan Z. Circadian Rhythm, Lifestyle and Health: A Narrative Review. Iranian journal of public health. 2018;47(8):1068-76.

22.          Manoogian ENC, Panda S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing research reviews. 2017;39:59-67.