Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

中文翻译：

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靶向细胞衰老可防止小鼠与年龄相关的骨质流失。

衰老与细胞衰老增加有关，据推测，这会导致多种合并症的最终发展。在这里，我们通过多种方法研究衰老细胞在与年龄相关的骨质流失中的作用。特别是，我们使用遗传（即编码在衰老细胞中特异性表达的诱导型半胱天冬酶 8 的 INK-ATTAC '自杀' 转基因）或药理学（即，'senolytic' 化合物）方法来消除衰老细胞。我们还使用 JAK 抑制剂 (JAKi) 抑制了衰老细胞促炎分泌组的产生。在已确定骨质流失的老年（20 至 22 个月大）小鼠中，在衰老细胞中激活 INK-ATTAC 半胱天冬酶 8 或用 senolytics 或 JAKi 治疗 2-4 个月导致更高的骨量和强度以及更好的骨微结构。与载体处理的小鼠相比，靶向衰老细胞的有益作用是由于骨吸收较低，骨形成维持（小梁）或骨形成较高（皮质）。体外研究表明，衰老细胞条件培养基损害成骨细胞矿化并增强破骨细胞祖细胞存活，导致破骨细胞生成增加。总的来说，这些数据确定了衰老细胞在随着衰老而骨质流失中的因果作用，并证明靶向这些细胞对骨骼具有抗再吸收和合成代谢作用。