Target Health Blog

Circadian Rhythms

July 30, 2018

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Overview of biological circadian clock in humans. Biological clock affects the daily rhythm of many physiological processes. This diagram depicts the circadian patterns typical of someone who rises early in morning, eats lunch around noon, and sleeps at night (10 p.m.). Although circadian rhythms tend to be synchronized with cycles of light and dark, other factors - such as ambient temperature, meal times, stress and exercise - can influence the timing as well.

Graphic credit: NoNameGYassineMrabetTalk fixed by Addicted04 - The work was done with Inkscape by YassineMrabet. Informations were provided from "The Body Clock Guide to Better Health" by Michael Smolensky and Lynne Lamberg; Henry Holt and Company, Publishers (2000). Landscape was sampled from Open Clip Art Library (Ryan, Public domain). Vitruvian Man and the clock were sampled from Image:P human body.svg (GNU licence) and Image:Nuvola apps clock.png, respectively., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3017148

A circadian rhythm is any biological process that displays an endogenous, entrainable oscillation of about 24 1) ___. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria. The term circadian comes from the Latin circa, meaning "around" (or "approximately"), and diem, meaning 2) ___. The formal study of biological temporal rhythms, such as daily, tidal, weekly, seasonal, and annual rhythms, is called chronobiology. Processes with 24-hour oscillations are more generally called diurnal rhythms; strictly speaking, they should not be called circadian rhythms unless their endogenous nature is confirmed. Although circadian rhythms are endogenous ("built-in", self-sustained), they are adjusted (entrained) to the local environment by external cues called zeitgebers (from German, "time giver"), which include light, temperature and redox cycles. In medical science, an abnormal circadian rhythm in humans is known as circadian 3) ___ disorder.

To produce the near 24 h rhythm in mammals requires a complex mechanism involving clock genes, clock proteins, phosphorylation of proteins, dimerization of proteins and subsequent degradation, and nuclear receptors. An internal 4) ___ also allows the multiple biochemical and physiological rhythms within the body to be aligned appropriately to each other. The activity of organs such as the stomach, liver, small intestine and pancreas and the blood supply to these organs need internal synchronization, and a clock can provide this co-ordination. To date, up to 20 genes and their protein products have been linked to the generation of circadian rhythms. At the heart of the molecular clock is a negative feedback loop, which in a very simplified description consists of the following sequence of events: clock genes are transcribed and their mRNAs are translated into proteins; the 5) ___ interact to form complexes, which move from the cytoplasm into the nucleus, where the transcription of the clock genes is inhibited; the inhibitory clock protein complexes are then degraded, and the core clock genes are once more free to make their mRNA and hence fresh protein, and so the cycle continues. This negative feedback loop generates a near 24 h rhythm of protein production and degradation, which encodes the biological day.

Although chronobiologists commonly study rhythms in constant conditions, organisms live in the cycling world of day and night. The two chief entraining stimuli that synchronize the endogenous clock with the exogenous temporal environment are 6) ___ and temperature. With the cloning of the Drosophila per gene, which encodes a novel protein of unknown function, the central question in clock research immediately became, "how can this gene product generate a circadian rhythm?" Negative feedback loops had been suspected to underlie the circadian clock, and several observations on per suggested that it might fit into such a loop. per mRNA abundance showed a circadian oscillation that was followed, with a lag of ~4 h, by oscillations in PER protein. As PER protein accumulated, per mRNA declined in abundance. This suggested a simple autoregulatory negative feedback 7) ___: the clock gene is transcribed and the transcript is translated into a protein that accumulates in the nucleus to inhibit further transcription. Degradation of both mRNA and protein relieves this inhibition, and the cycle renews. This simple model has largely withstood the test of time, although it has increased in complexity.

There are at least two interlocked feedback loops that include both positive and negative feedback. Positive components promote the transcription of negative components, and negative components play a dual role, blocking their own expression as well as increasing the expression of positive components, which interlocks the loops to create a robust sustained oscillation. This paradigm of interlocked transcriptional/translational feedback loops underpins the molecular mechanisms of the circadian clock in all eukaryotes studied to date. However, the combination of components recruited to form the clock varies among organisms; the fungal clock is quite distinct from the animal clock, although fly and mouse clocks are fairly similar. It is also clear that cyanobacteria provide a stunning exception to the essential ubiquity of transcriptional regulation in clock function, as a temperature-compensated circadian rhythm can be reconstituted in vitro with three Synechococcus proteins and ATP. Although we can safely conclude that the paradigm of interlocked feedback loops constituting a circadian oscillator is conserved in plants, not all the components have yet been identified, and the mechanistic details of almost every step are only incompletely understood. After so much effort and progress, almost all questions remain only incompletely answered and, effectively, all questions remain! Moreover, the field is now expanding its view from the purely reductionist goal of identifying the oscillator itself to a consideration of the evolutionary and ecological consequences of variation in clock function, so a host of new questions are being considered. It is exhilarating to consider what a retrospective view a decade from now will reveal.

Oxidative stress seems to have a circadian rhythm connection. The toxic effects of oxygen were first appreciated in 1954 with Gershman's free-radical theory, suggesting that oxygen toxicity may happen due to partially reduced forms of oxygen. Commoner et al., in the same year, suggested the presence of free radicals in a variety of biological materials. These new ideas triggered a surge of scientific research into the idea that although a necessary part of life, oxygen may not always be beneficial. The cell has evolved an intricate web of energy synthesis and signaling mechanisms that are dependent on oxygen and its more reactive forms, reactive oxygen species (ROS). Intense research has been done on ROS, their beneficial and detrimental effects on the organism, as well as the efforts mounted by the cell to counteract them. Interestingly, many of these efforts, including the production of antioxidants and protective enzymes, have been reported to be regulated by a biological clock or expressed in rhythmic fashions. The circadian clock system confers daily anticipatory physiological processes with the ability to be reset by environmental cues. This "circadian adaptation system" (CAS), driven by cell-autonomous molecular clocks, orchestrates various rhythmic physiological processes in the entire 8) ___. Hence, the dysfunction of these clocks exacerbates various diseases, which may partially be due to the impairment of protective pathways. If this is the case, how does the CAS respond to cell injury stresses that are critical in maintaining health and life by evoking protective pathways?

A short nap during the day does not affect circadian rhythms. Timing of medical treatment in coordination with the body clock, chronotherapeutics, may significantly increase efficacy and reduce drug toxicity or adverse reactions. A number of studies have concluded that a short period of sleep during the day, a power-nap, does not have any measurable effect on normal circadian rhythms but can decrease stress and improve productivity. 

Health problems can result from a disturbance to the circadian rhythm. 9) ___ rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness. A reversal in the sleep - wake cycle may be a sign or complication of uremia, azotemia or acute renal failure. Studies have shown that light has a direct effect on human health because of the way it influences the circadian rhythms. A great deal more research is needed to determine the interactions between biological clocks, human health and disease.

In 2017, the Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young "for their discoveries of molecular mechanisms controlling the circadian rhythm" in fruit 10) ___.

ANSWERS: 1) hours; 2) "day"; 3) rhythm; 4) clock; 5) proteins; 6) light; 7) loop; 8) body; 9) Circadian; 10) flies

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