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This artistic interpretation represents how weekly changes in the
light-dark cycle disrupts estrous cycles in middle-aged female mice.
Image Credit: Takasu et al./Cell Reports 2015

Infertility of middle-aged mice can be reversed

We all know our fertility cycle becomes more irregular during menopause. Now it appears our aging circadian clock may someday be reversible.

In a study published August 20 in Cell Reports, researchers in the United States and Japan found that fertility in middle-aged mice could be improved or reduced according to differences in the light-dark cycle, whereas younger mice remained unaffected.

Many of the body's processes follow a natural daily rhythm, our so-called circadian clock, based on a 24-hour day-night cycle. Previous research has shown that the menstrual cycle in female mammals responds to a region of the brain called the suprachiasmatic nucleus (SCN) which controls the circadian clock. Because of this relationship, researchers in Japan and the United States jointly investigated the phenomenon.

They found that genetic or environmental manipulations altering the SCN timing signal, disrupted the circadian rhythms of young female mice - but did not affect reproductive cycling and function. However, the same conditions led to infertility in older female mice.

"Importantly, changing the environmental conditions by matching periodicity of the light cycle to the altered periodicity of the SCN [suprachiasmatic nucleus] could restore reproductive function in older females."

Wataru Nakamura PhD, senior author, Laboratory of Oral Chronobiology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan

Although aging mammals are susceptible to reproductive dysfunction when changes occur in SCN signaling and thus the circadian clock, these effects might be reversed. While corresponding studies are needed to see if the same results apply to humans, the findings suggest that harmony between internal and environmental rhythms may help improve fertility.

"In modern society, females are exposed to many challenging perturbations in the environment that might play a role in fertility difficulties--we now live with high light levels in the evening, and our sleep cycle is disrupted by shift work or crossing time zones," said co-author Gene Block, of the University of California Los Angeles.

"The ability to rescue reproductive function by altering the light schedule in a rodent model suggests that improvements in 'circadian hygiene' — for example, reductions in evening illumination, more regular meal timing, or avoiding rotating shiftwork or schedules that lead to irregular sleep — may all be important remedies for reproductive difficulty."

Gene Block PhD, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California, USA

Abstract Highlights
•Environmental perturbation disrupts regular estrous cycles in middle-aged females
•Cry-deficient female mice show accelerated senescence of fertility
•Optimal circadian periods rescue female mice from age-related infertility

Summary
Female reproductive function changes during aging with the estrous cycle becoming more irregular during the transition to menopause. We found that intermittent shifts of the light-dark cycle disrupted regularity of estrous cycles in middle-aged female mice, whose estrous cycles were regular under unperturbed 24-hr light-dark cycles. Although female mice deficient in Cry1 or Cry2, the core components of the molecular circadian clock, exhibited regular estrous cycles during youth, they showed accelerated senescence characterized by irregular and unstable estrous cycles and resultant infertility in middle age. Notably, tuning the period length of the environmental light-dark cycles closely to the endogenous one inherent in the Cry-deficient females restored the regularity of the estrous cycles and, consequently, improved fertility in middle age. These results suggest that reproductive potential can be strongly influenced by age-related changes in the circadian system and normal reproductive functioning can be rescued by the manipulation of environmental timing signals.

Cell Reports, Takasu et al.: "Recovery from Age-Related Infertility under Environmental Light-Dark Cycles Adjusted to the Intrinsic Circadian Period" http://dx.doi.org/10.1016/j.celrep.2015.07.049

This work was supported by the Japan Science and Technology Agency PRESTO program.

Cell Reports, published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. For more information, please visit http://www.cell.com/cell-reports. To receive media alerts for Cell Reports or other Cell Press journals, contactpress@cell.com.

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