Abstract Multiple organ dysfunction is the most common cause of death in injured patients who do not die from brain injury or uncontrolled hemorrhage. Older patients are at highest risk for morbidity with reduced probability to return to productive life after trauma and shock. Current therapy is symptomatic without addressing the underlying mechanisms for the increased morbidity seen in aged individuals. In the past, we advanced the revolutionary idea that multiorgan dysfunction after trauma/shock is due to leak of the powerful digestive enzymes across the intestinal mucosal barrier systemically. Specifically, enteral blockade of digestive proteases in multiple forms of acute shock and sepsis significantly reduces diverse cell dysfunctions, morbidity and mortality; this intervention is currently being tested in FDA-approved Phase III clinical trial after completion of multiple successful Phase II studies in cardiac and gastrointestinal surgery patients. In this application we hypothesize and provide preliminary results that demonstrate chronic escape of digestive enzymes in old animals from the bowel into systemically, with subsequent infiltration into peripheral organs. Digestive enzymes cleave extracellular matrix proteins and membrane receptors, causing cell and organ dysfunctions in the old. When exposed to trauma/shock, the old are subjected to acute leak of digestive enzymes (just like the young) but in addition, must contend with a chronically accumulated digestive enzyme load in their tissues, leading to significantly increased multiorgan dysfunction after shock. Our Overall Objective is to use pretreatment of old rats with inhibitors of digestive enzymes prior to acute trauma/shock to reduce their high level of multiple organ dysfunction and mortality. Our Specific Aims are to (1) determine the accumulation and activities of digestive enzymes in tissues outside the gastrointestinal tract of old versus young rats of both genders. Preliminary results indicate that aged animals have significantly increased levels of digestive enzymes in peripheral tissues and consequently reduced organ function. (2) measure the protease activity and organ dysfunction in the old after treatment with digestive enzyme inhibitors. Our rationale is that one-week blockade of digestive enzymes with competitive inhibitors at low level (µM) reduces their activity in tissues outside the intestine and improves cell and organ function without significantly affecting digestive enzyme activity and digestion inside the small intestine (at mM concentrations). (3) determine multiorgan dysfunction and mortality after trauma/shock in pretreated old animals with attenuated digestive enzyme activity in their tissues outside the intestine. Our studies will bring to light a new mechanism for development of organ and cell dysfunction in the old that is translatable to humans. We will determine the first time the accumulation and temporal activity of digestive enzymes (including, b...