Disruptions to our circadian clocks - the internal molecular timekeepers "ticking" in nearly every cell of our body throughout the day - can lead to a wide range of health problems, from sleep disturbances to diabetes and cancer. But there has been no certainty about the identity of the body's substances that can "shift" these clocks forward or backward and, when altered, potentially cause such disruptions.
A new study from Prof. Gad Asher 's lab at the Weizmann Institute of Science, now published in Nature Communications , reveals that sex hormones play a central role in aligning the cellular clocks with one another and with the environment. The research team, led by Drs. Gal Manella, Saar Ezagouri and Nityanand Bolshette, showed that female sex hormones - especially progesterone - together with the stress hormone cortisol, have a dramatic effect on the clocks.
It is already known that circadian clocks are affected not only by external signals such as sunlight but also by signals carried through the bloodstream. Until now, however, these blood-borne signals had not been fully mapped, and there was no certainty about the component within the clock that serves as their "point of entry." The reason: Researchers lacked a precise method for tracking the clock's response to different signals over a full 24-hour cycle.
In recent years, Prof. Asher's lab - an international leader in studying the molecular mechanisms of circadian clocks - developed an ingenious method that uses an array of human cells each representing a different "time of day." It resembles a wall lined with clocks showing the current time in major cities around the world. The new approach enabled the researchers, for the first time and with unprecedented precision, to map how the cellular clocks are synchronized by blood-borne signals.
In addition to uncovering the influence of sex hormones, the study revealed that the clock component receiving these signals is the protein Cry2, rather than Per2, as previously believed.
"The levels of sex hormones change throughout life - during menstrual cycles, pregnancy, hormone therapy, contraceptive use and various disease states. These conditions are also known to be associated with disturbances to circadian clocks," Asher notes. "Our new findings suggest that these disturbances are linked to interactions between sex hormones and the mechanisms that synchronize circadian clocks."
Prof. Gad Asher's research is supported by the Dr. Barry Sherman Institute for Medicinal Chemistry.
