Aging and circadian dysfunction increase alcohol sensitivity and exacerbate mortality in Drosophila melanogaster

Alcohol abuse is a rising problem in middle-aged and older individuals resulting in serious health, family and economic consequences. Effective treatment necessitates the identification of factors influencing alcohol toxicity with aging. We investigated the interaction between aging, alcohol toxicity and circadian function using Drosophila as a model system. We found as wild type flies age, sensitivity to alcohol increases and circadian regulation of alcohol-induced behaviors weakens. Decreased circadian modulation is correlated with significantly greater alcohol sensitivity during the subjective day. The circadian clock modulates alcohol-induced mortality in younger flies with increased mortality following alcohol exposure at night. Older flies exhibit significantly longer recovery times following alcohol-induced sedation and increased mortality following binge-like or chronic alcohol exposure. Flies rendered arrhythmic either genetically or environmentally exhibit significantly increased alcohol sensitivity, longer recovery times and increased mortality. We hypothesize that the circadian clock phase specifically buffers behavioral and cellular alcohol sensitivity with this protection diminishing as the circadian clock weakens with age.