With increased life expectancy, debilitating diseases that accompany aging are also expected to rise, and one of them is dry eye disease. Increased age has repeatedly been associated with dry eye, although the precise mechanisms by which aging predisposes to dry eye disease remain unknown. Aging is accompanied by clinical, and sometimes sub-clinical chronic inflammation on the ocular surface and lacrimal gland (LG). The impact of age related dry eye disease is significant because it affects functional vision, as well as mobility, independence and the ability to perform daily tasks. Cathepsin S is a potent cysteine/protease expressed in the lysosomal compartments of both dendritic cells and LG acinar epithelia. Cathepsin S participates in physiological MHC II antigen presentation. Elevated levels of cathepsin S have been described in animal models and patients with Sjögren Syndrome and also in other animal models of autoimmunity, where it is thought to facilitate generation of autoreactive CD4+ T cells. Our preliminary data suggests that Cathepsin S is elevated in aging. However, the specific role of cathepsin S in the aged ocular surface and LG has not been elucidated. We hypothesize that age-related inflammatory changes in the ocular surface and LG lead to increased activity and production of cathepsin S by acinar epithelia and dendritic cells. This increased cathepsin S may 1) act in a paracrine fashion to amplify local inflammation and secretion of cytokines by the epithelium that can further increase cathepsin S creating a vicious circle; and 2) increase MHC II antigen presentation by aged dendritic cells, skewing them to prime pathogenic CD4+IFN-γ+ (Th1) cells that promote development of age-related dry eye disease. To investigate our hypothesis, we propose three specific aims: Specific Aim 1: how age-related inflammation in the ocular surface and LG stimulates cathepsin S production that promotes development of dry eye? Specific Aim 2: how age- related increase of cathepsin S modulates dendritic cell function and promotes the generation of autoreactive, pathogenic Th1 cells? Specific Aim 3: can cathepsin S inhibition modulate age-related dry eye? Results from these proposed experiments will improve our understanding of the fundamental mechanisms of age-related dry eye disease. Furthermore, it will change our view of aging on the ocular surface from an inevitable passive, degenerative process to an active, inflammatory and immune- mediated status that can be targeted, thus opening venues to prevent deleterious age-related dry eye.