Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults, reducing length and quality of life across the globe and inflicting a massive economic burden on society. Yet, despite decades of research, restoring protective immunity in older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of nave T (TN) cell numbers and function. Thus, rejuvenation of T cell function is highly desirable in order to enhance protective immunity and overall healthspan in older adults. This T cell Rejuvenation Program Project is centered on two key questions: (1) why do TN cell numbers and function deteriorate with age and; (2) what can be done about it? The premise of the program is that TN cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and the resulting decline in T cell production is an early event leading to immunosenescence. This reduction is compounded by a decline in TN cell maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against autoimmunity. Our goal is to identify mechanistic reasons behind reduced thymic function as well as impaired maintenance and activity of T cells in secondary lymphoid organs, such as lymph nodes, with aging. We will then develop combined strategies to ameliorate these defects in order to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects to both thymic production AND peripheral TN cell maintenance is required to formulate and test effective interventions for immune system rejuvenation in the elderly. Four integrated projects led by experts in the field, supported by four cutting-edge cores, will test this hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in thymic and secondary lymphoid organ aging; 2. Generate the Human-Mouse Timeline by comparing the progression of thymus, lymph node and T cell aging in mice and humans; 3. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 4. Devise and test rejuvenation strategies to improve 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 to preclinical models and, with the help of the Human-Mouse Timeline, be poised for translation to older adults.