Sjögren’s Syndrome (SS) is a chronic and debilitating systemic autoimmune disorder afflicting multiple organ systems. The targeting of the exocrine salivary and lacrimal glands by an autoimmune and inflammatory response leads to organ dysfunction causing reduced fluid secretion, which manifests into the dry mouth and dry eye symptoms of the disorder. Although a wide age range is reported in patients at diagnosis, it is well known that most SS patients are older. Why phenotypic traits are more prominent in older patients is unknown. Aging organs show heightened oxidative stress, which is often associated with declining organ function. Although,. SS patients show evidence of increased oxidative stress markers; whether elevated oxidative stress is causative or the outcome of an inflammatory response is unclear and challenging to investigate in patients. Hence based on published literature and our preliminary data, this proposal will test the overall hypothesis that the combined effects of autoimmunity and aging-associated oxidative stress contribute to salivary gland disease and dysfunction in SS. Aim 1 of this proposal will specifically address the hypothesis that aging-associated oxidative stress makes salivary glands more susceptible to immune-mediated damage. And in aim 2, by using a novel mouse model system, we will test the hypothesis that oxidative stress per se in salivary gland epithelial cells is insufficient to cause SS. The primary goal of this proposal is to understand the mechanisms behind key clinical observations in SS patients: prominence of clinical symptoms at an older age and the possible role of elevated oxidative stress in the disease process. Understanding basic mechanisms linking aging with organ dysfunction in SS will be essential in developing novel modalities to treat the disease.