Age-dependent neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and a variety of less common disorders, affect large numbers of individuals and are largely untreatable. Novel mechanisms of disease represent untapped potential for therapy development. Here we propose that anastasis (from the Greek, “rising from the dead”), or recovery from terminal caspase activation, represents a new mechanism inducing neuronal death in age-dependent neurodegenerative diseases. We present preliminary data derived from models of Alexander disease, an exemplar primary astrocyte mediated neurodegenerative disorder, to suggest that that anastasis drives neuronal death. We further capitalize on a valuable genome-scale genetic screen performed in an in vivo Drosophila model of Alexander disease to define mechanisms controlling glial anastasis and secondary non-cell autonomous neurodegeneration. We then test the hypothesis that anastasis contributes to neurodegeneration in Drosophila models of relevant to Alzheimer’s disease and related disorders. Finally, we examine mouse models of tauopathy for markers associated with anastasis. Our studies have the potential to define a new mechanism mediating neurodegeneration in aging-related disorders with accompanying opportunities for development of approaches to slow the onset and progression of neurological decline.