A new study published in Aging has shown a relationship between the circadian clock and the changes in gene expression with age.
Two complex systems and four distinct species
This study begins with an introduction to two complicated topics. The first is the circadian rhythm, the biological cycle that corresponds to the day-night cycle of our planet’s rotation. The second is aging. The goal of this study is to ascertain how aging influences this rhythm, potentially offering insight into ways that it might be restored in older people, who are known to suffer from sleep disorders and related issues [1].
The researchers chose four species to analyze: humans, mice, zebrafish, and an extremely short-lived species of killifish. They then subdivided these species into mature, older, and very old groups, based on the mean lifespan of each. For example, the researchers considered 60-year-old humans to be “old”, with 75-year-olds being “very old”. “Old” mice are two years old, while “very old mice” are three. Zebrafish live slightly longer than mice, and killifish live for slightly over half a year.
An analysis of gene expression
There were 46 circadian genes that were studied, including 9 core genes. Of these genes, the system regulator per2 and its repressor dec2 were found to be differentially expressed in all four of the studied species with age. The researchers note that, in addition to their circadian effects, per2 is associated with tumor suppression [2] and dec2 is related to multiple aspects of aging, including inflammation [3].
The researchers also analyzed the differential expression of genes in particular tissues. In gene expression, the livers of mice age much more quickly than the rest of the animal, and this fact was reflected in this study as well. The brain and skin of fish The researchers suggested that this is in accordance with previous studies [4], which show that, instead of being controlled by a master regulator as in mammals, each tissue uses its own circadian clock.
Age-related variance
Not only does gene expression itself change with age, the variability of this expression also changes in many genes. However, analyzing this change in the circadian genes in these four species yielded contradictory and confusing results. For example, in humans, the expression of these genes in skin begins to vary sharply in old age, however, in very old people, it returns to a level below that of mature individuals. Gene expression in murine skin varies sharply in very old age, but the variances reported in the blood and brains of mice resemble those of human skin.
While this particular analysis shows a statistically significant link between circadian gene expression and aging, this link is far from being well understood and the researchers are unable to explain these results. Clearly, a more in-depth, longitudinal study is required.
Conclusion
Unfortunately, while this study is of scientific interest and shows a clear relationship, it is difficult to draw any conclusions from it that are related to therapeutics. It may or may not be possible to directly influence dec2 and per2, particularly in the region of the hypothalamus that controls the circadian rhythm, in order to stabilize it; however, such a control would need to be rigorously studied and carefully monitored, as these genes have many other effects.
Literature
[1] Hofman, M. A., & Swaab, D. F. (2006). Living by the clock: the circadian pacemaker in older people. Ageing research reviews, 5(1), 33-51.
[2] Hua, H., Wang, Y., Wan, C., Liu, Y., Zhu, B., Yang, C., … & Halberg, F. (2006). Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer science, 97(7), 589-596.
[3] Imaizumi, T., Sato, F., Tanaka, H., Matsumiya, T., Yoshida, H., Yashiro-Aizawa, T., … & Satoh, K. (2011). Basic-helix-loop-helix transcription factor DEC2 constitutes negative feedback loop in IFN-ß-mediated inflammatory responses in human mesangial cells. Immunology letters, 136(1), 37-43.
[4] Isorna, E., de Pedro, N., Valenciano, A. I., Alonso-Gómez, Á. L., & Delgado, M. J. (2017). Interplay between the endocrine and circadian systems in fishes. Journal of Endocrinology, 232(3), R141-R159.
