NEJM blockbuster review: Biological clock and diseases

NEJM blockbuster review: Biological clock and diseases.  As these molecular associations are revealed, new interventions will be developed and applied to various systems affected by the biological clock.

In addition to determining the sleep-wake cycle and cognitive function, the biological clock also determines almost all physiological circadian cycles, such as blood pressure, heart rate, hormone levels, breathing, exercise capacity, and daily changes in blood clotting. Many pathological conditions occur at specific times of the day, which indicates that the circadian rhythm contributes to the disease.

The core function of the biological clock system is to drive energy acquisition and utilization according to the expected day and night cycle. Understanding the circadian rhythm at the molecular level helps us prevent and treat diseases.

On February 11, 2021, the New England Journal of Medicine (NEJM) published a review paper titled: Circadian Mechanisms in Medicine (Circadian Mechanisms in Medicine). The latest advances in medical research on circadian rhythms are introduced from the aspects of molecular mechanism, role in diseases, and diagnosis of circadian rhythm disorders.

Illumination synchronizes the biological clock with the earth’s 24-hour rotation. The pacing neuron is the master node of the biological clock hierarchical network, which drives the sleep-wake rhythm and coordinates the biological clock of peripheral tissues. The spontaneous firing rate and resting membrane potential of circadian rhythm pacing neurons show large diurnal changes. Neuronal activity can also reset the cell-autonomous molecular clock in the brain area outside the pacemaker cell, thereby maintaining the 24-hour synchronized oscillation of the entire main neural network.

Rod cells and cone cells, as well as specialized retinal ganglion cells (RGC) expressing the photosensitive pigment melanin, can transmit light information to synchronize the circadian clock of the hypothalamic suprachiasmatic nucleus (SCN). Artificial lighting at night will delay the biological clock, causing it to be out of sync with the environmental cycle, thus increasing the risk of sleep disorders. From summer to winter, as the length of the day changes, the consistency of daylight and SCN’s internal biological clock program changes, which leads to seasonal changes in the body cycle.

SCN pacing neurons regulate many physiological processes, including sleep, awakening, thermoregulation, autonomic nervous system tension, eating cycle, reward circuit, mood and movement. The central pacing circadian clock drives the rhythmic activity of the molecular clock expressed by most cells in the body, the latter is called the peripheral circadian clock. These peripheral biological clocks control a large number of molecular and cellular processes at almost every level of regulation.

Transcriptional analysis of animals, including humans, shows that a large part of the genome is controlled by the biological clock; more than half of the protein-coding genes exhibit different patterns of diurnal oscillations in various tissues. The circadian regulation of cell physiology originates from transcription and also from the rhythmic control of post-transcriptional processes, including RNA splicing, protein translation and post-translational processing.

The molecular circuit of the biological clock

The discovery of the Period gene (Per) of Drosophila melanogaster and the mouse Clock gene has made us a breakthrough in understanding how the biological clock “ticks” forward. Per encodes a protein that inhibits its own transcription, thereby generating rhythms. Later, we discovered the Per activation gene in mammals and named it Clock, which revealed that the gear of the biological clock is composed of activators that induce its own repressive gene expression, thus forming a highly conserved negative feedback from fruit flies to humans. Loop.

The core of this circuit consists of bHLH and PAS heterodimer transcription activators (CLOCK or NPAS2 and BMAL1) composition. In mammals, activating genes combine with E-box elements in core circadian clock repressor genes Period (Per1, Per2 or Per3) and cryptochrome genes (Cry1 or Cry2), and then make negative feedback to control their own transcription. The timing of feedback is regulated by post-transcriptional modifications (such as splicing and translation), especially post-translational modifications.

A common regulatory motif is the rhythmic phosphorylation and rhythmic degradation of circadian clock components. These processes are usually completed by the ubiquitin-proteasome system. This core loop is embedded in other transcriptional feedback loops through CLOCK-BMAL1 activating Rev-erbα and Rorα, thereby enhancing the core loop. Other transcription factors provide feedback and regulate CLOCK activity, including USF1 and Dec1-Dec2. Research on mice whose core biological clock has been disrupted has shown that the rhythm of physiological processes originates from the expression of oscillating genes located downstream of this core transcription oscillator.

Although the peripheral circadian clock is usually synchronized by the main SCN pacemaker, eating can independently synchronize the peripheral circadian clocks in the liver and kidney, so eating at an inappropriate time of the day will cause the circadian clock cycle to become unbalanced.

The role of circadian rhythm disorders in disease

Circadian rhythm disorders caused by artificial lighting, shifts and flying in airplanes are common in modern life, and promote many human diseases. Exposure to light at inappropriate times of the day will change the phases of the pacemaker neuron biological clock and peripheral tissue biological clock, and impair cognitive ability. Irregular sleep and eating can lead to imbalance in the biological clock of the metabolic organs, leading to obesity and diabetes. In addition, the incidence of disease-related events (such as myocardial infarction) and the efficacy after medication are usually affected by different times of the day.

sleep disorder

The circadian rhythm sleep disorder is characterized by the lack of synchronization between the circadian cycle in the body and the ambient light-dark cycle (Figure 2). These diseases may be caused by external conditions (such as crossing time zones or artificial lighting), or they may be caused by circadian clock dysfunction (such as mutations in core circadian clock genes). A serious subtype of circadian rhythm sleep disorder occurs in people who are blind due to bilateral eyeball removal. The above conditions cause people to lose their inherent photosensitive RGC, which makes SCN unable to perceive light signals.

Since the human body’s central circadian rhythm pacemaker can only change for about one hour a day, after flying across multiple time zones to reach the destination, the environment and the internal body clock will not be synchronized. Since the natural cycle of the biological clock is slower than 24 hours, the above problems are more obvious when flying eastward, because the biological clock needs to be accelerated to readjust to the new time zone. Working hours are one hour ahead of the biological clock (for example, when the clock is set one hour ahead of the daylight saving time), various adverse clinical conditions can also occur, including an increase in the incidence of myocardial infarction and an increase in movement disorders that cause car accidents.

The rework time difference after a vacation refers to the situation where the sleep time between working days and rest days is inconsistent. If you are exposed to blue light emitted by electronic equipment or other artificial lighting equipment at night (blue light can delay the time phase), the above problems will be aggravated.

The type of work and rest is heritable. Families that fall asleep very early can inherit mutations in the core biological clock gene (encoding casein kinase 1δ and its target PER2). CRY function gain mutations that reduce the activity of core circadian clock activators (CLOCK and BMAL1) have been identified as the cause of delayed falling asleep and prolonged awakening time. The disease is also associated with clock and Per3 polymorphisms.

Mental and neurodegenerative diseases

Sleep-wake behavior, daily rhythm disturbances at the level of hormones (such as melatonin) and gene expression (such as Per) are evident in patients with a variety of neurodegenerative diseases, including Huntington’s disease, Parkinson’s disease and Alzheimer’s disease . Preclinical and clinical studies have found an association between circadian rhythm disorders and neurotoxic protein accumulation and neurodegeneration itself. The circadian clock control of astrocyte and microglia function may also contribute to neurodegenerative diseases. The interaction between circadian rhythm and neurodegeneration may occur through the circadian clock control of sleep and the rhythmic clearance of neurotoxic proteins.

Biological clock disorders have been observed in schizophrenia and many other mental diseases. In terms of mechanism, the most prominent and most well-understood may be the relationship between circadian rhythm and mood disorders (such as seasonal affective disorder). These diseases are accompanied by a decrease in the amplitude or phase change of a variety of rhythms, including sleep-wake rhythm, blood pressure, hormonal rhythms (cortisol and melatonin), and 24-hour rhythmicity of the expression of biological clock genes. It is worth noting that the effect of mood disorder treatment is related to its ability to change the circadian rhythm. In fact, the antidepressant agomelatine directly targets the circadian rhythm system and has both agonist and antagonist effects, namely, melatonin receptor agonist and serotonin 2C (5-HT2C) receptor antagonism Agent. Human genetics research, including genome-wide association studies, has discovered circadian clock gene variants that can greatly increase the risk of mood disorders.

We have long recognized that in addition to being related to mania, light is also a factor in the occurrence of affective disorders. People who have symptoms of depression in the winter with short days and manic symptoms in the summer with long days are at the same end of the spectrum of light-sensitive mood disorders. At the epidemiological level, the incidence of depression and mania also corresponds to extreme latitudes. Blue light therapy for seasonal behavior disorders may be effective.

The regulation mechanism of light and the body clock on the mood is multi-factorial, and it is not yet fully understood. Animal model studies have revealed not only metabolic and immune pathways that may establish a correlation between the biological clock and mood regulation, but also specific molecular, cellular and physiological pathways (Figure 2 and Figure 3). The circadian clock genes directly regulate tyrosine hydroxylase and monoamine oxidase A, which are the rate-limiting enzymes in the production and degradation of dopamine, respectively. In view of the obvious role of dopamine in schizophrenia and many other mental diseases, the biological clock regulation mechanism may be suitable for new therapies.

cancer

Epidemiological and laboratory evidence suggests that cancer is associated with shifts and circadian rhythm disorders. There is evidence that colorectal disease and increased risk of breast cancer are associated with night shifts, and recent studies have shown that night light is associated with an increased risk of melanoma.

In addition, studies have shown that the interaction between the oncogenic bHLH transcription factors MYC and CLOCK can help regulate glycolytic genes, and this interaction may promote cancer progression in MYC-driven cancers such as neuroblastoma. The cross-flow between CLOCK-BMAL1 and HIF-1α is another node that assists in regulating circadian rhythm and metabolic pathways, and may be related to HIF-dependent cancers. Circadian rhythm disorders are not only related to the occurrence of cancer, but the disturbance of the rhythm may also cause DNA damage responses and other aspects of cancer progression. For example, the main output information of the biological clock involves the rhythmic control of enzymes involved in NAD+ biosynthesis, and NAD+ is a cofactor in the DNA repair pathway involving PARP and sirtuin deacetylase. In addition, CRY1 and CRY2 can inhibit nuclear receptors (such as androgen receptors) involved in endocrine cancer, which suggests potential therapeutic targets for prostate cancer.

Infection, inflammation and cardiovascular disease

There are diurnal changes in the innate immune cells of the circulatory system. The rhythm of the sympathetic nervous system also makes our response to endotoxin have rhythmic changes. In the epidermis, mast cells show diurnal changes in severe skin allergic reactions mediated by IgE. There are rhythmic changes in inflammatory bowel disease, which may be related to the circadian control of NFIL3, a typical repressor involved in the regulation of type 17 helper T cells. The joint symptoms of patients with rheumatoid arthritis in the morning can be attributed to the accumulation of inflammatory cytokines the night before.

There is inflammation in the process of cardiovascular disease and thrombosis, and it is affected by other circadian factors at the tissue and systemic level. Epidemiological evidence shows that myocardial infarction and aortic rupture are most frequent in the morning and when the biological clock changes with daylight saving time. The basic circadian rhythms that cause the high incidence of cardiovascular events in the morning include platelet activation, endothelial cell nitric oxide and thromboxane production, thrombo-promoting plasminogen activator inhibitor 1 production, and elevated catecholamine levels. Inherent electrical conduction and abnormal arrhythmia also peak in the morning. Recent evidence suggests that the risk of ischemia-reperfusion injury during cardiopulmonary bypass may be highest in the early morning.

Rhythm control disorders not only affect blood vessels, but the dysfunction of the biological clocks of adipose tissue, liver and muscle can subsequently promote cardiovascular metabolic disorders. In the muscle, the biological clock function regulates glucose uptake and exercise capacity, and these factors may affect the long-term cardiovascular risk. Many rate-limiting enzymes of cholesterol and bile acid metabolism in the liver show higher activity during the day, and the lack of synchronization between the cycle and eating in the body may promote dyslipidemia. In addition, the lack of synchronization between eating and the circadian cycle (the circadian cycle can regulate the insulin sensitivity of fat, nutrient storage, inflammation and thermogenesis) may contribute to metabolic complications and obesity.

Disturbances of glucose homeostasis and limited time eating

Impaired glucose tolerance is the main systemic effect of circadian rhythm disorders. Healthy people have lower glucose tolerance at night, while the “dawn phenomenon” (higher blood sugar levels in the morning) in diabetic patients reflects the continuous production of glucose and glucose uptake in the liver related to the stimulation of growth hormone, cortisol and adrenaline during sleep cut back.

The process of pancreatic β-cells releasing insulin requires the islet cells that can sense glucose to express genes of biological species. The circadian clock transcription factor regulates genes involved in insulin secretion and produces the maximum secretion capacity to synchronize it with wakefulness. The circadian control of the production of glucagon by alpha cells may be important for maintaining stable blood glucose levels during sleep.

Disturbances in eating time (genetically caused or simply due to increased high-fat diet) can lead to impaired glucose tolerance and weight gain, and limited time eating can improve metabolic disorders related to diet-induced obesity. Limiting the time period of eating can not only prevent obesity, but also achieve the metabolic characteristics observed when calorie intake is restricted, which suggests that it is possible to promote healthy aging by restricting eating time.

The normal circadian rhythm of the patient is often disrupted during hospitalization. For example, the light-dark cycle may be disrupted, and nutritional supplements may not be synchronized with the body’s circadian rhythm, and the body’s circadian rhythm is usually synchronized with light. These factors may promote inflammation and insulin resistance.

Diagnosis of circadian clock disorders

Although we have understood the profound impact of the biological clock on human diseases, the main obstacle to applying this knowledge to the clinic is that circadian rhythm disorders are very difficult to detect and diagnose. The standard method is to measure the timed rise in plasma melatonin levels. However, this operation requires continuous sampling, and usually must be performed at night and in dim light, so it is impossible to sample during the usual consultation time. Peripheral blood “omics” analysis has been combined with calculation tools to identify the circadian rhythm time label, so that the circadian rhythm phase can be accurately assessed, even with a single sample. These studies may open the door for routine clinical evaluation of circadian rhythm phenotypes, and may help predict drug efficacy and disease diagnosis and prognosis. An example is the range of circadian rhythm variables involved in blood pressure regulation, which may reflect differences in the types of work and rest between people.

We hope to detect specific changes in circadian rhythms to identify people who are at increased risk of disease and who are most likely to benefit from circadian rhythm therapy. Many pharmacological targets are products of inherently time-dependent RNA, including those involved in treatments that induce sleep or wakefulness, as well as those related to rhythm targets related to sex-producing hormones (such as glucocorticoids). For example, the circadian clock repressor gene CRY gene can rhythmically regulate the activity of nuclear receptors involved in neuroendocrine diseases (including prostate cancer).

Adjust the treatment plan according to the circadian rhythm

New evidence shows that synchronizing the time of medication with the body’s circadian rhythm can optimize the treatment effect. For example, adjusting the time of administration of oxaliplatin in a day can reduce off-target side effects for patients with colorectal cancer. Recently, there is evidence that the metabolism of small molecule receptor tyrosine kinase inhibitors has significant day-to-day changes, suggesting that considering the internal biological clock may enhance the efficacy of this drug and other chemotherapeutics. The rhythmic expression of central mitochondrial enzymes (important for the activation or catabolism of fat-soluble drugs) in the liver may affect the pharmacokinetics at different times of the day. The drug target itself may also reach its peak at different times. One example is that the rate-limiting enzyme HMG-CoA reductase in the process of cholesterol synthesis peaks at night, so we recommend taking short-acting statins at night. For many drugs with a half-life shorter than 12 hours, adjusting the medication time according to the circadian rhythm in the body can improve the efficacy.

Future challenges

Our current challenge is to understand the role of the biological clock in cells and tissues, and how to translate it into clinical practice. Research on the core mechanisms of the biological clock may help us develop therapies that reset or amplify the circadian rhythm signals. After understanding the relationship between molecular clock and disease from the mechanism, we can use it to determine the appropriate time for treatment and to discover new therapeutic targets. We predict that as these molecular associations are revealed, new interventions will be developed and applied to various systems affected by the biological clock.

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