User:Mntnhg/Chronodisruption

Introduction
Chronodisruption is a relatively new concept in the field of circadian biology. which refers to the disturbance or alteration of the body's natural biological rhythms, particularly 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 issues, including neurodegenerative diseases, diabetes , mood disorders , and even cancer. Such disruptors can lead to dysregulation of hormones and neurotransmitters, though research continues to fully understand the physical 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 new therapies, such as light therapy and pharmacological interventions, as well as lifestyle modifications, such as optimizing one’s sleeping environment and timing of meals and physical activity.

Chronodisruption in Model Organisms
Chronodisruption results in the misalignment between the natural light-dark cycle and timings of food intake, which would lead to the uncoupling of the master clock (entrained by light) and peripheral clocks (entrained by other signals such as feeding). The misalignment would lead to detrimental effects on metabolic health, including symptoms like insulin resistance, increased body mass, and accelerated aging. Chronodisruption is shown to have a causal relationship with cancer and tumor growth in animals. Chronodisruption is also correlated with an increased risk for cardiovascular disorders. Rodents are popular model organisms for the investigation of the role of chronodisruption in clinical areas including obesity, cancer and tumor, cardiovascular diseases, and reproduction.

Obesity
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. Studies showed that misalignment of timings of feeding with environmental cues may lead to significant weight gain.


 * Swiss Webster mice 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 light exposure at night also would have suppressed the melatonin level. 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. Thus, the relative melatonin deficiency due to light exposure at night may lead to obesity in chronodisrupted mice.
 * 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. Further human studies showed similar results.
 * Chronodisruption is often associated with shortened sleep. Studies using rodents demonstrate that sleep deprivation, which would lead to a reduced leptin level (the “satiety hormone") and an increased ghrelin level (the “hunger hormone"), would encourage 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.

Cancer and Tumor
Chronodisruption(e.g. caused by artificial light in the normal dark period, chronic jet lag, etc.) is demonstrated to have a causal role in cancer cell growth and tumor progression in rodents.


 * 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. 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, as melatonin is known to be an endogenously produced oncostatic agent that inhibits tumor cell growth via various potential mechanisms.
 * Extreme cases of chronic jet lag (6-hour advance every 7 days) 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. This finding may have great implications for shift workers and people that frequently experience transmeridian travels that advance their internal clock.

Cardiovascular Diseases
Experiments involving light-dark cycle manipulations, internal period mutations, and clock gene disruptions provide insights into the relationship between chronodisruption and the risk of cardiovascular diseases.


 * 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 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.

Reproduction
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 the idea that maternal plasma melatonin rhythm may drive the fetal rhythm.

Chronodisruption in Humans
Chronodisruption in humans, due to factors such as shift work, jet lag, social jet lag, or artificial light at night, has been associated with many health issues. These include metabolic disorders, neurodegenerative diseases , and cancer.

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.

Chronodisruption has also been implicated as a risk factor for neurodegenerative diseases such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). 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.

Chronodisruption, in the form of shift work, significantly 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.

Chronodisruption has been implicated in many other health issues, including - but not limited to - cardiovascular disease, ischemic stroke, compromised pregnancies, mental health disorders (bipolar disorder, depression, seasonal affective disorder, anxiety), osteoarthritis, rheumatoid arthritis, and multiple sclerosis.

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.

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, 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.

Claus Piekarski passed away on June 28, 2022, working at the University of Cologne until 2008, publishing several articles on cancer and chronodisruption.