Thymus is the core organ that reflects the degree of aging, and the anti-aging effect of rapamycin(RAPA) has been confirmed by multiple studies, but the dynamic changes of the thymus after the administration of RAPA have been lacking systematic research. Here, we observed the involution of thymus induced by RAPA (1 mg/kg/day, i.p. for 3 days) and its regeneration kinetics after withdrawal of RAPA, to explore the possible mechanism of RAPA’s anti-aging effects based on changes in thymus function. The results show that the thymus weight decreased by 46.15% post-RAPA, then regenerated from 20.45 mg to 57.97 mg, reaching 1.3-fold baseline levels in age-matched controls. RAPA can cause acute involution in thymic structure and function, such as loss of medullary thymic epithelial cells (mTECs) and subcapsular thymic epithelial cells (sTECs), abnormal differentiation of thymocytes, reduction of peripheral T cell proportion, and up-regulation of Foxn1 and Klf6 mRNA levels. Regeneration featured expanded double positive (DP) T cells, CD3 + TCRβ + T cells, CD8 single-positive (SP) T cells, medullary dilatation, and thymocyte telomere elongation. IL-7 and MET have pro-regeneration effects, but neither of them could accelerate RAPA-mediated thymic regeneration. IL-7 can prolong telomere length of thymocytes and restore peripheral T cell homeostasis, while MET can promote T cell positive selection and increase Sirt3 and Gimap4 mRNA levels. These results demonstrate that RAPA triggers transient thymic suppression followed by thymus volume and functional recovery. It seems that RAPA-mediated immune reconstitution may be an important reason for the potential anti-aging effect of RAPA.
As the main lymphoid organ, the thymus degenerates with age. The loss of thymic epithelial cells is mainly related to thymus degeneration and reduced T cells development. As an insulin sensitizer, metformin is a first-line drug for the treatment of diabetes and has been shown to prolong the lifespan of mice, but the mechanism is still unclear. In this study, we explored the therapeutic effect of metformin on thymus degeneration in the accelerated aging mice, which was established by intraperitoneal injection D-galactose (120 mg/kg/day) for eight weeks. Metformin was intragastrically given with 100 or 300 mg/kg body weight per day, respectively, for six weeks. Histological examination showed that metformin administration could alleviate thymus atrophy caused by D-galactose. In addition, metformin therapy increased mitochondrial membrane potential, with a reduction in mitochondrial reactive oxygen species, MDA and SOD levels, and restored mitochondrial balance through enhanced expression of dynamin-related protein 1 (Drp1). Furthermore, metformin altered T lymphocyte subsets and cellular senescent cells; the expression of FoxN1, Aire and Sox2 of thymic epithelial cells also increased. Thus, metformin presented a positive effect on thymic degeneration through improving mitochondrial function. Taken together, these findings revealed an unexpected complexity in the anti-aging of this widely used drug.
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