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      Lowered Insulin Signalling Ameliorates Age-Related Sleep Fragmentation in Drosophila

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          Abstract

          Reduced insulin signaling improves sleep quality in flies and is protective against age-related sleep deterioration.

          Abstract

          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 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.

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          Most cited references38

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          Neural mechanisms of ageing and cognitive decline.

          During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
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            Role and regulation of starvation-induced autophagy in the Drosophila fat body.

            In response to starvation, eukaryotic cells recover nutrients through autophagy, a lysosomal-mediated process of cytoplasmic degradation. Autophagy is known to be inhibited by TOR signaling, but the mechanisms of autophagy regulation and its role in TOR-mediated cell growth are unclear. Here, we show that signaling through TOR and its upstream regulators PI3K and Rheb is necessary and sufficient to suppress starvation-induced autophagy in the Drosophila fat body. In contrast, TOR's downstream effector S6K promotes rather than suppresses autophagy, suggesting S6K downregulation may limit autophagy during extended starvation. Despite the catabolic potential of autophagy, disruption of conserved components of the autophagic machinery, including ATG1 and ATG5, does not restore growth to TOR mutant cells. Instead, inhibition of autophagy enhances TOR mutant phenotypes, including reduced cell size, growth rate, and survival. Thus, in cells lacking TOR, autophagy plays a protective role that is dominant over its potential role as a growth suppressor.
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              Autophagy in metazoans: cell survival in the land of plenty.

              Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                April 2014
                1 April 2014
                : 12
                : 4
                : e1001824
                Affiliations
                [1 ]Max Planck Institute for Biology of Ageing, Cologne, Germany
                [2 ]Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
                Stanford University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: AM LST SG LP. Performed the experiments: AM LST SG. Analyzed the data: AM LST SG LP. Wrote the paper: AM LST SG LP. Performed qPCRs: UB OH. Performed mass spectrometry: YH.

                Article
                PBIOLOGY-D-13-04954
                10.1371/journal.pbio.1001824
                3972082
                24690889
                cc163709-b3d9-47b2-baae-5eb7560f01a7
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 December 2013
                : 13 February 2014
                Page count
                Pages: 13
                Funding
                This work was funded by the Max Planck Society and Wellcome Trust ( http://www.wellcome.ac.uk) Strategic Award: Genomic and biochemical analysis of ageing and age-related disease 081394/Z/06/Z. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement n° 268739. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Molecular Cell Biology
                Neuroscience
                Behavioral Neuroscience
                Medicine and Health Sciences
                Neurology
                Sleep Disorders
                Research and Analysis Methods
                Model Organisms
                Animal Models

                Life sciences
                Life sciences

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