Circadian rhythms - mechanism of our internal clock

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"The golden chain that ties health and our bodies together" - Thomas Dekker

Dissecting the mechanism of our internal clock:

How living organisms tune in to the time of day

From the National Center for Biotechnology Information

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=coffeebrk.chapter.13

As any jet-setter knows, it takes time to adapt to the shifted day-night cycle of a foreign time zone. We have an internal circadian clock that times many physiological and behavioral events on a 24-hour cycle, according to day length. The clock can also reset itself, so we can cope with the seasonal variation in day light hours and the trappings of 20th century living such as shift work and air travel.

Not only humans have circadian rhythms. The eyes of marine molluscs, for example, show a correlation between perception of light and a circadian rhythm, as do the pineal glands of lizards and birds. The underlying clock that gives rise to these rhythms is dependent on feedback loops that regulate the expression of certain genes. Two animals in particular have given insight into the molecular mechanisms of internal clocks: the fungus Neurospora crassa and the fruit fly Drosophila melanogaster.

Several components of molecular clocks have now been cloned and sequenced. In Neurospora, the frq gene was the first found to be associated with period length; then two more genes, wc-1 and wc-2, were discovered in a strain of Neurospora that was blind to light. Both wc-1 and wc-2 are transcription factors that contain zinc fingers and transcriptional activation domains. Furthermore, these two proteins have PAS domains.

PAS domains were first identified in the Drosophila period clock protein PER, the vertebrate aryl hydrocarbon receptor nuclear translocator (ARNT), which is involved in a cell's response to lowered oxygen levels, and the Drosophila single-minded protein (SIM1), involved in the regulation of development. Many proteins have since been found to have PAS domains, which have now been shown to mediate protein-protein interactions.

A series of recent papers have confirmed that there is a common pattern to molecular clocks that has been conserved across evolution, from fungi to mammals. Part of the pattern is that PAS domains glue proteins such as wc-1 and wc-2 together to form a complex that switches on other clock components, such as frq, as a part of the organism's response to light. The frq protein then feeds back to inhibit the action of wc-1 and wc-2, thereby ultimately effecting its own expression. Signals from the environment, such as different light levels or temperature, could impact upon the loop to add more layers of regulation.

There are certain to be more feedback loops that are linked to this core component, because several observations have been made that do not quite fit this model, and it is not yet clear whether the clocks of plants or cyanobacteria will work in the same way. Perhaps these other cogs will be specific to different organisms, with only the "master clock", outlined here, being conserved across species.

Time will tell.

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Length of the Body's Clock

Is the human circadian clock slightly longer than a day? It’s long been thought to be about 25 hours in young adults, but the length seems to shorten with age. That was the going theory for decades and explained why old people went to bed earlier and get up earlier than young people. It wasn’t just learned behavior, but stuff like hormones,

It is now felt that there is no significant difference in the correlation in the circadian day between young and old people. Changes in the SCN could be due to a disease rather than a normal consequence of aging. The ILP Workship Report: Sleep, Health, and Aging cites polysomnographic work showing a decline in deep sleep (slow wave) from 18.9% of total sleep time during ages 16 to 25 to only 3.4% during midlife. Growth hormone levels also declined.

As people age from middle age to older ages, there is not a further decline in slow wave sleep. However, REM Sleep (stage 5) decreases in late life and sleep fragmentation increases. The ILC Workshop Report claims "the presence of disturbed sleep predicts overall health-related quality of life better than any other disease-activity measure in patients who suffer chronic illness."

The suprachiasmatic nucleus in the brain is known to be bound up in the body’s circadian rhythm. As people age, there are changes to the afferent (nerves from the SCN to the cortex) and efferent (to the SCN).