GW9508-Induced Activation of GPR40 in Thymic Epithelial Cells: A Therapeutic Strategy to Delay Thymic Aging

Age-associated thymic involution leads to a reduction of T-cell production, which constitutes a primary factor in immunosenescence, thereby increasing vulnerability to cancer, infections, and autoimmune disorders. Thymic epithelial cells (TECs), essential for T-cell development, exhibit progressive senescence with aging. The development of strategies to mitigate TECs senescence and delay thymic degeneration has emerged as a significant research focus. Here, aged C57BL/6J mice and immortalized thymic epithelial cells (iTECs) were hired. The marked reduction of GPR40 expression was observed in TECs from aged mice and in senescent iTECs induced by doxorubicin in vitro. Administration of the GPR40 agonist GW9508, antagonist GW1100, or their combination to aged mice or senescent iTECs demonstrated that GPR40 activation effectively restored thymic function in aged mice. Mechanistically, GW9508 targeted GPR40 to elevate intracellular calcium ion levels, thereby activating the AMPK signaling pathway and inhibiting the hyperactivation of the ERK1/2-MAPK pathway in senescent cells, ultimately enhancing the activity of aged iTECs. Collectively, these findings suggest that the exogenous activation of GPR40 by GW9508 may represent a viable strategy to alleviate thymic senescence and enhance immune function in aged individuals.