Lowered Insulin Signalling Ameliorates Age-Related Sleep Fragmentation in Drosophila

Sleep fragmentation, particularly reduced and interrupted night sleep, impairs the quality of life of older people. Strikingly similar declines in sleep quality are seen during ageing in laboratory animals, including the fruit fly Drosophila. We investigated whether reduced activity of the nutrient- and stress-sensing insulin/insulin-like growth factor (IIS)/TOR signalling network, which ameliorates ageing in diverse organisms, could rescue the sleep fragmentation of ageing Drosophila. Lowered IIS/TOR network activity improved sleep quality, with increased night sleep and day activity and reduced sleep fragmentation. Reduced TOR activity, even when started for the first time late in life, improved sleep quality. The effects of reduced IIS/TOR network activity on day and night phenotypes were mediated through distinct mechanisms: Day activity was induced by adipokinetic hormone, dFOXO, and enhanced octopaminergic signalling. In contrast, night sleep duration and consolidation were dependent on reduced S6K and dopaminergic signalling. Our findings highlight the importance of different IIS/TOR components as potential therapeutic targets for pharmacological treatment of age-related sleep fragmentation in humans. Author Summary Sleep is essential for human health, but the quality of this fundamental physiological process declines with age and reduces quality of life. We therefore investigated the mechanisms by which ageing impairs sleep. We used the fruit fly Drosophila, whose sleep has many features in common with that of humans, including the age-related decline in quality. We examined the role of the insulin/IGF (IIS) and TOR signaling network, which has an evolutionarily conserved role in ageing. We found that flies with reduced IIS activity had improved sleep quality at night and higher activity levels by day. Importantly, day activity and night sleep were regulated through distinct mechanismsday activity by the key IIS transcription factor dFOXO, adipokinetic hormone, and octopaminergic signallingwhereas night sleep was mediated through TOR and dopaminergic signalling. Surprisingly, acute inhibition of TOR, by rapamycin, even in old flies, improved sleep quality, suggesting that age-related sleep decline is reversible even after it has commenced. Given the high evolutionarily conservation of IIS and TOR function, our results implicate potential therapeutic targets to improve sleep quality in humans.