Project Summary We discovered that sleep deprivation causes accumulation of free radicals (reactive oxygen species, ROS) and oxidative stress in the gut of flies and mice. This is in large part responsible for the premature death seen when sleep is very low. Here we propose to study what occurs upstream and downstream of ROS accumulation. Specifically, we will ask how the lack of sleep leads to increase in ROS, and how ROS then causes organismal death. Together, this will bring us closer to fully understanding what sleep does for health and longevity. This is an important problem as so many of us are chronically sleep deprived, and sleep deprivation causes or exacerbates a whole slew of diseases.