Circadian regulation of metabolism and healthspan in Drosophila.

Abstract

Circadian clocks generate daily rhythms in gene expression, cellular functions, physiological processes and behavior. The core clock mechanism consists of transcriptional-translational negative feedback loops that turn over with an endogenous circa 24h period. Classical genetic experiments in the fly Drosophila melanogaster played an essential role in identification of clock genes that turned out to be largely conserved between flies and mammals. Like in mammals, circadian clocks in flies generate transcriptional rhythms in a variety of metabolic pathways related to feeding and detoxification. Given that rhythms pervade metabolism and the loss of metabolic homeostasis is involved in aging and disease, there is increasing interest in understanding how the clocks and the rhythms they control change during aging. The importance of circadian clocks for healthy aging is supported by studies reporting that genetic or environmental clock disruptions are associated with reduced healthspan and lifespan. For example, arrhythmia caused by mutations in core clock genes lead to symptoms of accelerated aging in both flies and mammals, including neurodegenerative phenotypes. Despite the wealth of descriptive data, the mechanisms by which functional clocks confer healthspan and lifespan benefits are poorly understood. Studies in Drosophila discussed here are beginning to unravel causative relationships between the circadian system and aging. In particular, recent data suggest that clocks may be involved in inducing rhythmic expression of specific genes late in life in response to age-related increase in oxidative stress. This review will summarize insights into links between circadian system and aging in Drosophila, which were obtained using powerful genetics tools available for this model organism and taking advantage of the short adult lifespan in flies that is measured in days rather than years.