Infectious disease cancer and autoimmune disorders affect hundreds of millions of older adults reducinglength and quality of life across the globe and inflicting a massive economic burden on society. Yet despitedecades of research restoring protective immunity in older adults has remained elusive. One critical factorcontributing to age-related immune decline is a loss of nave T (TN) cell numbers and function. Thusrejuvenation of T cell function is highly desirable in order to enhance protective immunity and overallhealthspan in older adults. This T cell Rejuvenation Program Project is centered on two key questions: (1) why do TN cell numbers andfunction deteriorate with age and; (2) what can be done about it? The premise of the program is that TN cellaging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and theresulting decline in T cell production is an early event leading to immunosenescence. This reduction iscompounded by a decline in TN cell maintenance and function in the periphery. These deficiencies combine toerode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells andto properly guard against autoimmunity. Our goal is to identify mechanistic reasons behind reduced thymicfunction as well as impaired maintenance and activity of T cells in secondary lymphoid organs such as lymphnodes with aging. We will then develop combined strategies to ameliorate these defects in order to improveimmune defense in the elderly. Our hypothesis is that mechanistic dissection of defects to both thymicproduction AND peripheral TN cell maintenance is required to formulate and test effective interventionsfor immune system rejuvenation in the elderly. Four integrated projects led by experts in the field supported by four cutting-edge cores will test thishypothesis and achieve the following Program Goals: 1. Define mechanistic changes in thymic and secondarylymphoid organ aging; 2. Generate the Human-Mouse Timeline by comparing the progression of thymuslymph node and T cell aging in mice and humans; 3. Determine the endogenous regenerative capacity ofthymic and secondary lymphoid organ stroma over the lifespan; 4. Devise and test rejuvenation strategies toimprove thymopoiesis and peripheral T cell maintenance and function so as to enhance protective immunity. Over this support period the above goals will provide a wealth of basic knowledge that will be translated topreclinical models and with the help of the Human-Mouse Timeline be poised for translation to older adults.