Abstract
Author SummarySleep 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 mechanisms—day activity by the key IIS transcription factor dFOXO, adipokinetic hormone, and octopaminergic signalling—whereas 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.
Highlights
Increased human life expectancy has brought with it an increased burden of age-related loss of function and pathology, including sleep disorders, which affect,50% of the population over 65 years old
Loss of forkhead Box O (FOXO) Affected Day Behaviours of insulin receptor dominant negative (INRDN) Flies To identify molecular mechanisms that mediated the activity and sleep phenotypes of insulin-like growth factor (IGF) signalling (IIS) mutants, we investigated the role of the transcription factor dFOXO, which is essential for lifespan extension by reduced IIS in Drosophila [12]. dfoxo/dilp2-3,5 double null mutants are lethal, but dfoxo/INRDN double mutants are viable
In conclusion, reduced IIS extends lifespan in diverse organisms
Summary
Increased human life expectancy has brought with it an increased burden of age-related loss of function and pathology, including sleep disorders, which affect ,50% of the population over 65 years old. Mutants that reduce insulin/ insulin-like growth factor (IGF) signalling (IIS) can extend healthy lifespan in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and the mouse, and may ameliorate human ageing [6,7,8]. Down-regulation of TOR signalling by the TOR-specific inhibitor rapamycin extends lifespan in flies and mammals [16,17]. It is not clear if reduced IIS and/or TOR activity can delay neural and behavioural senescence, because increased activity in the nervous system itself can be neuroprotective in specific disease states [18], and extended lifespan is not invariably accompanied by amelioration of age-related loss of behavioural function [19].
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