Bone marrow stromal/stem cells (BMSCs) are generally considered as common progenitors for both osteoblasts and adipocytes in the bone marrow, but show preferential differentiation into adipocytes rather than osteoblasts under aging, thus leading to senile osteoporosis. Accumulated evidences indicate that rejuvenation of BMSCs by autophagic enhancement delays bone aging. Here we synthetized and demonstrated a novel autophagy activator, CXM102 that could induce autophagy in aged BMSCs, resulting in rejuvenation and preferential differentiation into osteoblasts of BMSCs. Furthermore, CXM102 significantly stimulated bone anabolism, reduced marrow adipocytes, and delayed bone loss in middle-age male mice. Mechanistically, CXM102 promoted transcription factor EB (TFEB) nuclear translocation and favored osteoblasts formation both in vitro and in vivo. Moreover, CXM102 decreased serum levels of inflammation and reduced organ fibrosis, leading to a prolonger lifespan in male mice. Our results indicated that CXM102 could be used as an autophagy inducer to rejuvenate BMSCs and shed new lights on strategies for senile osteoporosis and healthyspan improvement.

骨髓基质/干细胞（BMSCs）通常被认为是骨髓中成骨细胞和脂肪细胞的共同祖细胞，但在衰老过程中优先分化为脂肪细胞而不是成骨细胞，从而导致老年性骨质疏松症。越来越多的证据表明，通过自噬增强使骨髓间充质干细胞年轻化可以延缓骨衰老。在这里，我们合成并证明了一种新型自噬激活剂CXM102，它可以诱导衰老的BMSCs发生自噬，从而使BMSCs恢复活力并优先分化为成骨细胞。此外，CXM102 显着刺激中年雄性小鼠的骨合成代谢，减少骨髓脂肪细胞，并延迟骨质流失。从机制上讲，CXM102 促进转录因子 EB (TFEB) 核转位，并在体外和体内有利于成骨细胞的形成。此外，CXM102 降低了血清炎症水平并减少了器官纤维化，从而延长了雄性小鼠的寿命。我们的结果表明，CXM102 可用作自噬诱导剂，使 BMSC 恢复活力，并为老年骨质疏松症和改善健康寿命的策略提供新的思路。