Cellular mechanisms underlying age-associated changes in sleep and oxidative homeostasis

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Project Summary Sleep is an evolutionarily conserved behavior across the animal kingdom. In both humans and model organisms, a lack of sleep leads to illness and even death. Moreover, in both humans and model organisms, aging leads to changes in sleep patterns and declines in sleep quality. Declining sleep quality is also associated with many age-related diseases, such as Alzheimer’s disease in humans. Therefore, sleep is thought to play an essential role in healthy aging. Age-related diseases are also associated with increased biomarkers of oxidative stress, a state of elevated reactive oxygen species (ROS) and cellular oxidative damage. Using Drosophila melanogaster, the Shirasu-Hiza lab previously showed that sleep promotes defense against oxidative stress. Given these data, my central hypothesis is that sleep acts in specific tissues to activate cellular oxidative stress response pathways and that, as sleep quality declines with age, these oxidative stress defenses weaken and allow age-related pathophysiologies. Because the underlying mechanisms remain unclear, I propose to identify sleep-induced cellular mechanisms that defend against oxidative stress and determine how these change with normal aging and in Alzheimer’s disease models. I will use Drosophila melanogaster, an advantageous model organism for this work because mechanisms underlying both sleep and oxidative stress are conserved from flies to humans and there are established Drosophila models of Alzheimer’s disease. Aim 1 will identify specific tissue(s) in which sleep promotes defense against oxidative stress and determine if these are more vulnerable with age. ROS levels and oxidative damage will be assessed in tissues of young short-sleeping flies relative to controls and compared to middle-aged and old flies. Aim 2 will examine how sleep quality modulates the oxidative stress state and phenotypes of Alzheimer’s disease models. Levels of ROS, oxidative damage, and survival after acute oxidative stress will be used to assess the oxidative stress state of Alzheimer’s model flies with induced or deprived sleep relative to unmanipulated Alzheimer’s disease flies and control. Disease severity will be assessed through lifespan, mobility, and protein aggregation. Aim 3 will investigate specific cellular mechanisms by which sleep promotes defense against oxidative stress and how these change with age. RNA-sequencing will be employed to probe the transcriptional differences between short-sleeping flies and controls under normoxia and hyperoxia, high oxygen treatment. Significantly differentially expressed genes and/or pathways will be assessed for their functional role in sleep-promoted defense against oxidative stress in middle-aged and old flies, as well as Alzheimer’s models. Together, these experiments will determine the cellular connection between sleep and oxidative stress defense and how this relationship changes with age and Alzheimer’s disease pathology. This will improve our understanding of aging, Alzheimer’s disease, and the therapeutic potential of sleep.