Degeneration of the thymic epithelium is believed to be the primary cause of age-associated thymic involution. In order to investigate the molecular events during the early phase of thymic involution, RNA-seq was performed to gain the transcriptional profiles of medullary thymic epithelial cells (mTEC) from mice of 2, 6 and 10 weeks of age. We confirmed and extended the previous observation of declined expression of cell cycle-related genes and diminished E2F3 activity during thymic involution, showing that it occurred as early as 2–6 weeks after birth. Moreover, we demonstrated that mTEC aging was coupled with augmented expression of inflammatory chemokines and cytokines, reminiscent of the senescence-associated secretory phenotype. Impaired cell cycling and proinflammatoty response therefore represent two predominant transcriptional signatures during the very early phase of thymic involution. Taken together, the present study provides not only complimentary information about, but also new insight into the molecular mechanisms underlying age-related degeneration of thymic epithelial cells.