Aging Circadian Clock and Its Effects on Alcohol Sensitivity and Toxicity

Excessive alcohol consumption in middle-aged and older individuals is a growing concern as 72% of alcohol-poisoning deaths occur in adults 35 years and older. Treating alcohol-related pathologies requires an understanding of the factors affecting alcohol toxicity and the mechanisms through which these factors modulate behavioral and cellular responses to alcohol. One of the factors potentially underlying age-related pathologies is the weakening of the circadian system with age. Circadian rhythms are internally driven cycles that rise and fall during the 24-hour day. Circadian clocks are present in almost all animals and plants on earth and coordinates rhythms in gene expression, metabolism, hormone secretion and cellular signaling. As individuals age, circadian rhythms weaken and become more susceptible to internal desynchronization. This dissertation presents research that investigates how the circadian regulation of alcohol sensitivity and toxicity changes with increased age and identifies changes in the clock that affects this sensitivity and toxicity in middle and old age. The model system used to investigate these effects is Drosophila melanogaster, a powerful genetic system with highly conserved signaling mechanisms, well-established for studies intersecting aging, circadian biology and alcohol neurobiology. My research data demonstrate that the circadian clock modulates the behavioral responses to alcohol with the greatest sensitivity observed during the night. Aging increases the sensitivity and toxicity to alcohol’s effects and dampens the circadian regulation of alcohol sensitivity and toxicity. An intact clock is necessary to buffer the toxic effects of alcohol. Entrainment of the circadian clock using the alternative temperature entrainment pathway is sufficient to reduce alcohol toxicity and facilitate induction of short-term and long-term rapid tolerance in older flies. The strength of the light-entrainment pathway is diminished in older flies. Selectively over-expressing cryptochrome (cry) in oscillatory cells is sufficient to lower alcohol mortality and facilitate the expression of short-term but not long-term tolerance in older flies suggesting the requirement of other transcriptional changes, circadian or perhaps non-circadian for the induction of long-term tolerance in older flies. Temperature entrainment of the clock substantially consolidates the rhythms in sleep-wake activity in older flies and pharmacologically inducing sleep in middle-aged and older flies lowers alcohol-related mortality. These results suggest that targeting the circadian clock may be a viable therapeutic option for mitigating alcohol pathologies in older individuals.