撰文丨王聪 编辑丨王多鱼 排版丨水成文 大脑健康 与 骨骼稳态 密切相关。骨骼衰老的特征是骨形成不足和骨髓脂肪过多，但大脑是否导致了这种 骨脂失衡 （ bone-fat imbalance ） ，目前仍不得而 知。 在这项最新研究中，研究团队发现，衰老的大脑神经元 （主要是海马体和大脑皮层中的神经元） 会产生过量的 WDFY1 蛋白，并通过 细胞外囊泡 （EV） 将其转 运到 骨骼 中，进而导致 骨脂失衡 （ bone-fat imbalance ） 和 骨质疏松 （ osteoporosis ） 。 研究团队进一步证实，大脑中 Wdfy1 基因表达增加会导致骨骼过早衰老。相反，在整个大脑、海马体或神经元中抑制 Wdfy1 基因表达 ，在神经元中敲除 Wdfy1 基因，以及选择性抑制神经元的细胞外囊泡释放，均可改善骨骼健康。 从机制上来说，WDFY1 与 R etromer 复合体结合，促进组织蛋白酶 D （ cathepsin D ） 和过氧化还原酶-2 （ peroxiredoxin 2 ） 从 内体向高尔基体的 再循 环，从而抑制成骨作用并促进脂肪生成。 总的来说，该研究揭示了衰老大脑神经元的细胞外囊泡 ...

Core Viewpoint - Cellular senescence is a stable state of growth arrest closely related to age-related diseases and cancer development, characterized by an intrinsic anti-apoptotic ability and a unique secretory phenotype known as the senescence-associated secretory phenotype (SASP) [1][2]. Group 1 - Senescent tumor cells release mitochondrial DNA (mtDNA), which enhances immunosuppression mediated by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) through the cGAS-STING pathway [3][9]. - The release of mtDNA from senescent cells can exacerbate inflammation associated with tissue damage or disease progression, indicating a potential mechanism linking cellular senescence to age-related diseases and cancer [2][6]. - The study highlights that targeting the release of mtDNA could reprogram the immunosuppressive tumor microenvironment, thereby improving cancer treatment outcomes for patients undergoing chemotherapy [9][10]. Group 2 - The research team found that both naturally senescent primary cells and tumor cells undergoing senescence due to treatment actively release mtDNA into the extracellular environment [5][7]. - Extracellular mtDNA is encapsulated in extracellular vesicles and selectively transferred to PMN-MDSC, enhancing their immunosuppressive activity through the cGAS-STING-NF-κB signaling pathway [5][10]. - Pharmacological inhibition of voltage-dependent anion channels (VDAC) can reduce extracellular mtDNA levels and reverse PMN-MDSC-driven immunosuppression, improving chemotherapy efficacy in prostate cancer mouse models [6][10].