Aging is the most significant health and economic risks facing society today. As aging adversely affects both homeostatic and regenerative replacement of cells, the maintenance of the functional and structural integrity of tissues and organs is severely compromised resulting in chronic disease. This has profound implications for stem cell therapy in aged individuals including those suffering salivary gland dysfunction and dry mouth due to surgery, disease, and therapeutic radiation for head and neck cancer. However, despite the vast majority of patients with salivary dysfunction aged 45yrs or older and the well described adverse alterations in salivary gland structure and function that occurs with increasing age, the effects of aging on stem cell behavior during salivary gland homeostasis and regeneration are not known. in the Knox lab, we propose to define the regenerative capacity of aging stem cells and the mechanisms impairing tissue regeneration. We have recently identified SOX2 as a marker of progenitors that replenishes acini in response to parasympathetic nerve derived acetylcholine. Our preliminary data indicates that functional parasympathetic nerves as well as the number of SOX2+ cells and their homeostatic capacity decreases with age in human and murine SG. Conversely, sympathetic innervation as well as inflammatory macrophages, increase with age, resulting in an autonomic and immune imbalance. Based on these outcomes, the extensive evidence that bi-directional communication between the nervous system and immune system is essential to tissue homeostasis and repair, we hypothesize that aging causes an imbalance in autonomic innervation of the SG that impairs SOX2-mediated homeostasis and regeneration and immune cell regulation. We will address our central hypothesis via three specific aims: 1) Determine whether enhancing parasympathetic innervation can improve regenerative capacity and reduce inflammation in aging SG 2) Elucidate how sympathetic innervation impacts acinar cell replacement and inflammation during SG aging and 3) Determine if inflammatory macrophages reduce parasympathetic function and promote sympathetic hyperinnervation in aging SG. These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with epigenetic, biochemical, immunochemical, and high resolution imaging techniques. Our rationale for investigating this hypothesis is that understanding the effects of aging on the homeostastic and regenerative capacity of stem/progenitor cells and on processes that regulate their behavior is vital to their therapeutic application in reversing salivary dysfunction.