Thymic aging in the absence of klotho (HEM4P.243)

Age-related thymic involution, characterized by a decrease in thymic epithelial cell (TEC) proliferation, absolute number, and organization, results in overall defective support of T cell development and proliferation and is a major cause of thymic dysfunction. Using a genetic model of advanced aging caused by deficiency of Klotho, an anti-aging gene and modifier of FGF signaling, we investigated TEC-intrinsic aging in the absence of a globally aging environment. By one month of age, Klotho deficient (Kl-/-) mice display a disrupted thymic architecture, a 4-6 fold decrease in TEC numbers, as well as significant decreases in all thymocyte populations and also a 3-8 fold decrease in peripheral T cell numbers. To separate thymus-intrinsic aging from the effects of organismal aging, we implanted fetal thymi from Kl-/- mice under the kidney capsule of mice lacking thymi. Kl-/- and WT fetal thymi supported comparable levels of thymopoiesis as measured by the numbers of T cells in peripheral blood and lymphoid organs up to 4 months post-implantation, with both cohorts of implants not detectable past 5 months. In this aging model, isolation from the systemic effects of Klotho deficiency attenuates age-related thymic dysfunction, suggesting that extrathymic factors affect thymic aging.