Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution.
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 gamma (PPARgamma), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARgamma in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARgamma-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.
Yang
Hyunwon
H
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Youm
Yun-Hee
YH
Dixit
Vishwa Deep
VD
D050156:Adipogenesis / Q000235:genetics / Q000276:immunology*; D000375:Aging / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000821:Animal Feed; D000818:Animals; D031204:Caloric Restriction / Q000379:methods; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000276:immunology; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000276:immunology; D014968:Xanthine Dehydrogenase / Q000096:biosynthesis / Q000502:physiology
D006131:Growth Inhibitors; D047495:PPAR gamma; D014968:Xanthine Dehydrogenase