Effects of Aging on the Molecular Circadian Oscillations in Drosophila

Abstract

Circadian clocks maintain temporal homeostasis by generating daily output rhythms in molecular, cellular, and physiological functions. Output rhythms, such as sleep/wake cycles and hormonal fluctuations, tend to deteriorate during aging in humans, rodents, and fruit flies. However, it is not clear whether this decay is caused by defects in the core transcriptional clock, or weakening of the clock-output pathways, or both. The authors monitored age-related changes in behavioral and molecular rhythms in Drosophila melanogaster. Aging was associated with disrupted rest/activity patterns and lengthening of the free-running period of the circadian locomotor activity rhythm. The expression of core clock genes was measured in heads and bodies of young, middle-aged, and old flies. Transcriptional oscillations of four clock genes, period, timeless, Par domain protein 1ϵ, and vrille, were significantly reduced in heads, but not in bodies, of aging flies. It was determined that reduced transcription of these genes was not caused by the deficient expression of their activators, encoded by Clock and cycle genes. Interestingly, transcriptional activation by CLOCK-CYCLE complexes was impaired despite reduced levels of the PERIOD repressor protein in old flies. These data suggest that aging alters the properties of the core transcriptional clock in flies such that both the positive and the negative limbs of the clock are attenuated. (Author correspondence: [email protected])

Keywords:

• Aging
• Circadian clock
• Clock gene expression
• Drosophila

ACKNOWLEDGMENTS

We are grateful to Eileen Chow for help with qRT-PCR in fly bodies and locomotor activity analysis. We thank Jeff Price for gift of anti-PER, and Amita Sehgal for sharing unpublished data. This research was supported by NIH 1R21AG038989 and R21-NS-075500 grants to J.M.G, and Jagiellonian University K/ZDS/001964 grant to E.P. K.R. is supported by NSF IGERT in Aging Sciences Fellowship at Oregon State University (DGE 0965820).

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.