Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China.
Int J Mol Sci. 2023 Mar 31;24(7):6554. doi: 10.3390/ijms24076554.
Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from , delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.
越来越多的证据表明，衰老细胞（SCs）在衰老生物体中的负担增加在许多与年龄相关的疾病中起着重要作用。用“衰老细胞清除剂”（senolytics）来消除 SC 的药理学方法已经成为治疗与年龄相关疾病和延长健康寿命的新疗法。在本研究中，我们发现环黄芪醇（CAG），一种从黄芪中分离得到的次级代谢产物，通过其对 SC 的衰老细胞清除活性来延缓小鼠的与年龄相关的症状。通过筛选一系列化合物，我们发现 CAG 通过诱导 SC 细胞凋亡选择性地杀死 SC，这个过程与 Bcl-2 抗凋亡家族蛋白和 PI3K/AKT/mTOR 通路的抑制有关。此外，CAG 处理还抑制了 SC 中衰老相关分泌表型（SASP）的发展，从而抑制了由 SASP 介导的细胞迁移。此外，用 CAG 对接受辐射诱导衰老的小鼠进行 2 周的处理，减轻了 SC 的负担，并改善了动物与年龄相关的身体功能障碍。总的来说，我们的研究表明 CAG 是一种具有体内活性的新型衰老细胞清除剂，有可能用于治疗与年龄相关的疾病。
