NEW insights into the mechanisms of the circadian clock suggest that circadian regulation is directly connected to cellular stress. The findings, from scientists at the University of Tokyo, Tokyo, Japan, display the crucial role a family of genes play by adjusting their internal body clock to enable cells to adapt their sleep-wake cycles to changes in environmental conditions.
It is hoped this work will aid the eventual development of therapies that regulate circadian rhythms when there are problems with this mechanism; when such issues occur, they can contribute to the development of numerous diseases, including hypertension, metabolic disorders, and insomnia. People whose circadian clock is frequently disrupted, such as shift workers and the elderly, are particularly vulnerable to such conditions.
Assistant Prof Hikari Yoshitane, University of Tokyo, said: “The dream is to have a tool to regulate circadian rhythms. Basic science like our research can show hints for later drug discovery work.”
In the study, the researchers found that three genes (Ask1, Ask2, and Ask3) were needed to adapt the circadian clock both to sudden changes to the environment and gradual changes over time. In cells that lacked these genes, there was no synchronisation of their circadian rhythm to environments with too high or low concentrations of salt or sugar. Likewise, no adaptation was observed to the changes expected following the accumulation of too much oxidative stress in the cells; this causes changes in chemical balance, potentially creating toxic environments.
These results were supported by observations in mouse models. While those mice with the Ask genes could adapt their wake-up time in the morning following unexpected exposure to light in the night, mice without the genes had less ability to change their body clocks.
Prof Yoshitaka Fukada, University of Tokyo, commented: “We are very excited about our results because we can approach the origin of the circadian clock by connecting oxidative stress and circadian regulation through the Ask genes.”
The team are now planning to study the detailed cellular mechanisms connecting Ask genes to oxidative stress, in addition to evaluating ways in which the circadian rhythm can potentially be influenced.
James Coker, Reporter
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