Inhibition of Ectopic Adipocyte Accretion within Aging Thymic Environment Stimulates Thymopoiesis

Abstract

With advancing age, the thymic lymphoid and stromal cell microenvironment is progressively replaced with adipocytes, leading to reduction in output of naive T cells in a process recognized as thymic involution. Using magnetic resonance imaging we demonstrate that compared to 25 year old healthy adults, by 45 years of age greater than 75% of human thymus is replaced with adipose tissue. Herein, we report an age‐related increase in epithelial to mesenchymal transition (EMT) in thymus and further differentiation of thymic fibroblasts to adipocytes by activation of PPARγ, and aP2 pro‐adipogenic pathways. The stromal cells undergoing adipogenic transformation were unable to support the T cell development of lymphoid progenitors. The thymus specific inhibition of PPARγ, aP2 by means of pro‐longevity intervention, caloric restriction reversed adipogenic progression. Reduction of EMT genes in aging thymus by CR led to regeneration of cortical epithelium and thymic vessels at cortico‐medullary junction with increased early thymocyte progenitors naïve T cell output and improvement of peripheral T cell receptor diversity. Up regulation of EMT genes and specific gain of function of PPARγ and aP2 pathway in thymic stromal cell in absence of ghrelin signaling increased thymic involution. Collectively, these data suggest that inhibiting the pro‐adipogenic pathways within thymus could offer a new mechanism to forestall thymic aging and promote renewal.