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Laboratory of Neuroendocrine-Immunology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808
Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor 
(PPAR), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPAR in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPAR-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the Coypu and Pennington Foundation grants to V.D.D. The present work utilized the facilities of the Genomics and Cell Biology and Bioimaging Core facilities supported by National Institutes of Health (NIH) Grant P20 RR-021945 and Cell Biology and Bioimaging Core Facility of the Pennington Biomedical Research Center’s Center of Biomedical Research Excellence and Clinical Nutrition Research Unit (NIH P30 DK072476).
2 Address correspondence and reprint requests to Dr. Vishwa Deep Dixit, Laboratory of Neuroendocrine-Immunology, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail address: Vishwa.Dixit{at}pbrc.edu
3 Abbreviations used in this paper: CR, calorie restriction; AL, ad libitum; DL1, Delta-like-1; EMT, epithelial-mesenchymal transition; ETP, earliest thymocyte progenitor; EVA, early V antigen; FABP4/aP2, fatty acid-binding protein-4; FSP-1, fibroblast-specific protein-1; MDI, 3-isobutyl-1-methylxanthine and dexamethasone with insulin; PDGF, platelet-derived growth factor; PPAR, peroxisome proliferator-activated receptor ; TEC, thymic epithelial cell; TREC, TCR excision circle; TSC, thymic stromal cell; XOR, xanthine oxidoreductase.
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  H. Yang, Y.-H. Youm, B. Vandanmagsar, J. Rood, K. G. Kumar, A. A. Butler, and V. D. Dixit Obesity accelerates thymic aging Blood, October 29, 2009; 114(18): 3803 - 3812. [Abstract] [Full Text] [PDF]
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