# Chronodisruption

Chronodisruption is a concept in the field of circadian biology that refers to the disturbance or alteration of the body's natural biological rhythms, for example the sleep-wake cycle, due to various environmental factors. The human body is synchronized to a 24-hour light-dark cycle, which is essential for maintaining optimal health and well-being. However, modern lifestyles —which involve exposure to artificial light (especially during nighttime), irregular sleep schedules, and shift work — can disrupt this natural rhythm, leading to a range of adverse physiological outcomes. Chronodisruption has been linked to a variety of health disorders and diseases, including neurodegenerative diseases, diabetes, mood disorders, cardiovascular disease, and cancer. Such disruptors can lead to dysregulation of hormones and neurotransmitters, though researchers continue to investigate the physiological implications of chronodisruption. Indeed, research in chronobiology is rapidly advancing, with an increasing focus on understanding the underlying mechanisms of chronodisruption and developing strategies to prevent or mitigate its adverse effects. This includes the development of pharmacological interventions, as well as lifestyle modifications such as optimizing one's sleeping environment and timing of meals and physical activity.

## Chronodisruption and Cancer

People with chronodisruption have increased risk for certain types of cancer. Chronodisruption is demonstrated to have a causal role in cancer cell growth and tumor progression in rodents. In 2020, the International Agency for Research on Cancer (IARC) found that chronodisruption due to chronic night-shift work is a probable carcinogen (cancer-causing agent) in humans.

### In Humans

* Chronodisruption, in the form of shift work, increases the risk of breast cancer in women by about 50%. The risk of developing other forms of cancers, such as prostate cancer in men and colorectal cancer in women, may also increase with chronodisruption; studies in this area have shown modest, but statistically significant, associations. Chronodisruption is associated with impeded homeostasis of the cell cycle; this is correlated with malignant growth acceleration and cancer, potentially due to obstruction of normal DNA damage repair.

### In Model Organisms

* In the studies investigating the relationship between experimental chronic jet lag and tumor progression done by Filipski et al., mice were kept under either 12:12 Light-Dark cycles (LD cycles) or under 12:12 LD cycles that would phase-advance by eight hours every two days. Upon injection with Glasgow osteosarcoma cells, a rapid acceleration in cancer cell proliferation rate was observed in the mice experiencing an 8-hour phase advance every two days compared to the mice not experiencing phase advance. Moreover, clock gene expressions (e.g. mPer2) were suppressed in mice subjected to repeated phase advance, while the daily rhythm in clock gene expression was maintained in mice in a typical 12:12 LD cycle. The down-regulation of the p53 gene and over-expression of the c-Myc gene associated with the clock disturbance may also have contributed to tumor progression.
** Melatonin is known to be an endogenously produced oncostatic agent that inhibits tumor cell growth via various potential mechanisms. Studies showed that perfusing the human breast cancer xenografts growing in animals in melatonin-rich blood collected from premenopausal women significantly inhibited all signs of rapid cancer cell proliferation. On the other hand, melatonin-deficient blood collected from the same set of women failed to restrict tumor growth. In the originals studies done by Filipski et al., a mouse strain named B6D2F$_1$, which had a low level of circulating melatonin, was used. Although no definite conclusion can be made on the possible effects of melatonin on cancer development in B6D2F$_1$ mice based on the original studies, a general statement can be made: besides the direct effects of internal desynchronization with the external environment, the accelerated rate of cancer cell proliferation may also be a consequence of relative melatonin deficiency caused by chronodisruption.
* Extreme cases of chronic jet lag (6-hour advances every week last equal to or more than 4 weeks under experimental setting) were observed to cause premature death in aged male mice compared to their counterparts kept in stable external LD cycles. This consequence was not observed in mice experiencing chronic phase delays. This showed that persistent internal desynchronization as a result of repeated phase advances may be associated with reduced longevity. The findings may have great implications for shift workers and people that frequently experience transmeridian travels that advance their internal clock.
* Recent studies since 2016 in mice have shown that chronic jet-lag models accelerates tumorigenesis in genetic models of lung cancer, liver cancer, colorectal cancer, and skin cancer. It has been suggested that chronodisruption is an "Hallmark of Systemic Disease".

## Chronodisruption and Cardiovascular Disease

Chronodisruption is correlated with an increased risk for cardiovascular disease in humans. Experiments involving light-dark cycle manipulations, internal period mutations, and clock gene disruptions in rodents provide insights into the relationship between chronodisruption and the risk of cardiovascular diseases.

### In Humans

* Chronodisruption is associated with a significantly increased risk of cardiovascular disease in humans. Shift work has been implicated as a major risk factor for coronary heart disease, hypertension, ischemic stroke, and sudden cardiac death. Social jet lag, discrepancy between the schedule of working days and free days or misalignment between biological time and social time, may also be associated with increases in cardiovascular disease risk, as evidenced by increased triglyceride levels, decreased high-density lipoprotein-cholesterol levels, and decreased insulin sensitivity.

### In Model Organisms

* Mice exposed to a shortened 10:10 LD cycle (20-hour cycle) were observed to exhibit symptoms of abnormal cardiac pathophysiology, including decreased levels of cardiomyocytes and vascular smooth muscle cell hypertrophy, compared to mice in a typical 12:12 LD cycle (24-hour). These symptoms were rescued when the mice were subsequently exposed to the typical 24-hour LD cycle. Mutant mice with a 22-hour intrinsic period were affected with symptoms of cardiomyopathy and early death as a result when put under a 24-hour LD cycle; however, their cardiac functions were normalized under a shortened LD cycle (22-hour cycle) that matched their intrinsic period.
* Experiment simulating "shift-work" in mice (keep mice awake for 6 hours during their inactive period for several days) showed that mice misaligned with the external LD cycle had decreased metabolic efficiency and disrupted cardiac function.
* Deletion or mutation of core clock genes (e.g. Bmal1, Clock, Npas2) was shown to have an adverse impact on cardiac function, including attenuating glucose utilization, accelerating cardiomyopathy, and reducing longevity.

## Chronodisruption and Metabolic Disorders

Food is a strong Zeitgeber for peripheral clocks, and the timing of food intake can disrupt or amplify the coordination between the central pacemaker and peripheral systems. This misalignment can lead to detrimental effects on metabolic health, including symptoms like insulin resistance and increased body mass.

### In Humans

* There is an increased risk of Type 2 Diabetes associated with shift work, with even higher risks among rotating shift or night shift workers and health care workers. Chronodisruption has been shown to disturb the regulation of glucose and insulin in the body, providing a potential pathway for this increased risk.
* Additionally, shift workers exhibit a higher risk for obesity than day workers, which increases with the number of years exposed and the frequency of shifts. It is hypothesized that circadian regulation of hormonal secretion related to appetite, as well as the presence of circadian clocks in adipose tissue cells, may influence the increased obesity risk related to shift work, although further study will be necessary to confirm this pathway.
* Timing of the food intake matching the proper circadian phase is also essential. Cross-sectional studies done by Wang et al. demonstrated that people who consumed ≥ 33% of their daily energy intake in the evening were two-fold more likely to become obese than those who received their energy intake in the morning. Hence, timing of food intake is also correlated with obesity.

### In Model Organisms

* Swiss Webster mice (an all-purpose mouse strain used as a research model) that have altered timings of food intake due to exposure to artificial light at subjective night gained weight substantially beyond the control mice that were placed under a regular light-dark cycle.
** The experimental design that included light exposure at night would have led to a reduction of nighttime melatonin level and disturbed the melatonin rhythm. Melatonin was suggested to have anti-obesity effects due to its ability to stimulate the growth and metabolic activity of Brown Adipose Tissue, inducing weight loss. The relative melatonin deficiency due to light exposure at night may lead to obesity. However, melatonin level was not measured in the original experiments. More recent articles also suggested that the majority of laboratory mouse strains, including the Swiss Webster mice, do not produce melatonin on their own. Thus, the role of melatonin in the metabolic consequences of circadian misalignment caused by altered timings of food intake remains unclear.
* Mice fed with a high-fat, obesogenic diet showed dampened rhythms in feeding and dampened hepatic circadian rhythms, promoting hyperphagia and obesity. Studies investigating the effect of isocaloric time-restricted feeding (TRF) discovered that mice fed with a high-fat diet (HFD) in an 8-to-12-hour window during the normal feeding time (subjective night) had significantly less weight gain than the mice fed with HFD during the time when feeding is normally reduced (subjective day). This observation in mice suggested that the timing of food intake is associated with obesity.
* Chronodisruption is often associated with shortened sleep. Studies using rodents demonstrate that sleep deprivation, which leads to a reduced leptin level (the "satiety hormone") and an increased ghrelin level (the "hunger hormone"), encourages increased food intake.
* Experiments investigating clock gene mutants and knockouts show the strong linkage between obesity, metabolic disorders, and the circadian clock. ClockΔ19 mice with disrupted circadian rhythm (Clock gene mutant mice) have dampened diurnal feeding rhythm and are obese. ClockΔ19 mice with leptin knockout are significantly more obese than mice with leptin knockout only, implying the significant contribution of chronodisruption to obesity in mice. Similarly, mPer2-knockout mice fed a high-fat diet were significantly more obese than their wild-type counterpart.

## Chronodisruption and Reproduction
### In Humans

* Chronodisruption, in the form of shift work, has been associated with disturbances in menstrual period (increased irregularity and length of cycles) and mood. This deterioration of the menstrual cycle has also been shown to increase with increasing duration of chronodisruption.
* Chronodisruption during pregnancy is also associated with various negative outcomes, including low relative birth weight, preterm birth, and miscarriage.

### In Model Organisms

* Chronodisruption has a detrimental effect on the reproduction and development of offspring in rodents. Both clock gene mutations and experiencing phase advances or delays after copulation were observed to interfere with the ability to complete pregnancies. Deletion of the key clock gene, Bmal1, in mouse ovaries significantly reduces oocyte fertilization, early embryo development, and implantation.
* Gestational chronodisruption (clock misalignment during pregnancy) induced by chronic phase shift is linked with detrimental effects on the health of mouse progeny, including persistent metabolic, cardiovascular, and cognitive dysfunctions. However, these conditions were reversed when the chronodisrupted mother received melatonin in the subjective night, suggesting that maternal plasma melatonin rhythm may drive the fetal rhythm.

## Chronodisruption and Neurodegenerative Diseases
### In Humans

Chronodisruption has also been implicated as a risk factor for neurodegenerative diseases such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) in humans.
* Circadian regulation of metabolism and dopamine levels are hypothesized to contribute to the link between chronodisruption and PD.
* Increased risk for AD may be influenced by increased levels of t-tau protein in the blood due to sleep loss, as well as certain AD-risk genes which are suggested to be controlled by the circadian clock, though these factors are still under investigation.
* Sleep loss in pre-pathological stages of AD might be correlated with future pathological progression, including the increase of Amyloid-beta 42 in cerebrospinal fluid.

### In Model Organisms

* The misalignment between the sleep/wake cycle and feeding rhythms in mice causes circadian desynchrony between the SCN and hippocampus. Mice exposed to "jet lag" experimental conditions experience circadian misalignment, exhibiting an increased amount of inflammatory markers in blood, diminished hippocampus neurogenesis, and impaired learning and memory.
* Being exposed to altered LD cycles (e.g. 10:10 LD cycle) also disrupts SCN-mediated rhythms and causes peripheral metabolic alterations in mice, leading to decreased dendritic branching of cortical neurons, decreased cognitive flexibility, and behavioral impairments.

## Notable Researchers

Chronodisruption first became a notable concept in 2003 when three researchers from the University of Cologne in Germany, Thomas C. Erren, Russel J. Reiter, and Claus Piekarski, published the journal, Light, timing of biological rhythms, and chronodisruption in man. At the time, Erren, Reiter, and Piekarski were studying how biological clocks can be used to understand cycles and causes of cancer, suggesting that cancer follows a rhythmic light cycle. These three men are considered to have conceived the term "chronodisruption", making large conceptual strides from "chronodisturbance", and even further, "circadian disruption". Circadian disruption is a brief or long period of interference within a circadian rhythm. Chronodisturbance is the disruption of a circadian rhythm which leads to adaptive changes, leading to a less substantial negative impact in comparison to chronodisruption, which leads to disease. Another notable researcher in the field is Mary E. Harrington.
Thomas C. Erren is currently still employed by the University of Cologne, where his research focuses on intersections between chronobiology and disease in terms of prevention.
Russel Reiter is employed by UT Health, San Antonio and involved in processes of aging and disease, specifically how oxygen interacts with neurodegenerative diseases. His research group is also studying properties of melatonin, its relations with circadian disruptions, and the resulting physiology.
Mary E. Harrington is employed by Smith College, where she is the head of their neuroscience program. Her research is focused on the impact of disruptions to the central and peripheral clocks, as well as the impact of disruptions on Alzheimer's and aging.