SUMMARY Lifespan and aging-associated neurodegenerative conditions, such as Alzheimer’s disease, are thought to be controlled by internal (genetic) and external (environment) factors. We propose that the interactions with microorganisms are an important environmental factor. Animals are constantly infected by microorganisms, but whether infection and the associated immune responses affect lifespan and aging-related diseases is poorly understood. The overall goal of this project is to examine the effect of RNA virus infection on aging and Alzheimer’s disease in the model organism Drosophila melanogaster. A large body of work supports the idea that major features and principles of innate immunity and aging are conserved in evolution and Drosophila has proven to be an excellent system to understand both innate immunity and aging. Our lab has established multiple models of chronic and acute infection viral in Drosophila. Aging and neurodegeneration in flies are associated with innate immunity activation, but previous research focused on acute pathogenic or commensal bacteria. Chronic infections are common in animals, but the effects of continued activation of antiviral responses on senescence have not been well defined. We propose to define the links among chronic viral infection, innate immunity, Alzheimer’s disease and provide mechanistic insights into the neurodegenerative process. We will characterize the acceleration of aging in chronically infected individuals and test its mechanistic underpinnings and consequences for other aging phenotypes, such as susceptibility to Aß in Alzheimer’s disease. The excellent models for aging and Alzheimer’s disease in Drosophila will allow us to examine the mecanistic links between these processes. Our preliminary experiments show that chronic viral infection leads to an accelerated aging of the transcriptome accompanied by a shortened lifespan. This transcriptome analysis implicated two major pathways in aging and viral infection: Nonsense-mediated decay (NMD) and the integrated stress response (ISR). We have organized the proposal into three specific aims: Aim 1 focuses on immunosenescence, a progressive aging-related decline in the immune system and the effects of chronic RNA virus infection on lifespan and aging-associated diseases. Aim 2 will determine the links among infection, aging and NMD and ISR pathways. We expect that these studies will provide critical information on the linkages among infection, immunity, aging and neurodegeneration.