Project Summary The major goal of this project is to elucidate how stress negatively impacts health and accelerates aging. In both animals and humans, repeated activation of the fight or flight response increases disease susceptibility and reduces lifespan. How it does so is not well understood. In mammals, stress disorder symptoms are associated with high levels of stress hormones such as adrenaline, which are released by the sympathetic nervous system in response to acute stress. However, the complexity of the nervous system and the multifaceted stress response in mammals makes the study of how the flight response impairs health and accelerates aging an exceedingly difficult task. We propose to address this critical question in the nematode Caenorhabditis elegans. The genetic tractability, short lifespan, and relatively simple nervous system make C. elegans an exceptional model to uncover mechanisms of stress physiology. We recently showed that neural stress hormones that are released during the C. elegans flight response negatively impact animal´s health and lifespan by activating the insulin pathway. We found that early larval stages are particularly sensitive to the negative health impacts of the flight response. The flight response in C. elegans triggers the release of tyramine, the invertebrate analog of adrenaline. Tyramine activates an adrenergic-like receptor in the intestine, which in turn leads to the stimulation of the DAF-2/Insulin/IGF-1 signaling (IIS) pathway. Stimulation of the DAF-2/IIS pathway inhibits the activation of multiple cytoprotective transcription factors that enhance stress resistance. In contrast, long-term environmental stressors, such as heat, starvation or oxidative stress, reduce tyramine release and inhibit IIS, thereby promoting the expression of cytoprotective genes. Tyramine thus provides a state-dependent neural switch between the acute flight and long-term environmental stress response. The link between neural stress hormones and the insulin pathway provides a completely novel paradigm to understand how the perpetuated activation of the flight response negatively affects health and shortens lifespan. We propose to combine genetics, pharmacology, behavioral analysis and imaging techniques in C. elegans to elucidate how the flight response activates the insulin pathway and negatively affects cytoprotective defense mechanisms. The aims of the proposal are 1: Determine how neural stress hormones modulate ILP secretion from non-neuronal cells to inhibits cytoprotective mechanisms; 2: Identify neural circuits that inhibit the release of neural stress hormones; 3: Determine the mechanisms that underlie long-lasting impacts of early-life stress on health and aging. Completion of these aims will provide a deep understanding into elusive mechanisms of neural modulation of the stress response. We anticipate that new mechanistic insights into the neural control of the stress response in the worm will be similarly rele...