Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)–lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre+/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre+/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre+/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.

中文翻译：

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自噬通过 LepR+ 基质细胞调节与年龄相关的颌骨丢失


骨老化和自噬活性降低是相关的，但在颌骨中探索不足。本研究旨在表征衰老的颚骨和颌骨衍生的基质细胞 （JBSC），并确定自噬在颌骨质量下降中的作用。我们观察到老年人和小鼠的颚骨表现出相似的年龄相关骨质流失。此外，瘦素受体 （LepR） 谱系细胞是体外培养和扩增的 JBSCs（称为 LepR-Cre+/JBSCs）的主要来源。来自颌骨和 LepR-Cre+/JBSCs 的 RNA 测序数据显示，磷酸肌醇 3-激酶 （PI3K）/蛋白激酶 B （AKT）/哺乳动物雷帕霉素靶标 （mTOR） 通路在衰老过程中表达上调。通过单细胞转录组学，我们确定了衰老骨组织中 LepR 谱系细胞中成骨谱系细胞比例和 PI3K/AKT 通路激活的降低。老年小鼠 （O-小鼠;O-JBSCs）。药物和组成型自噬激活减轻了 O-JBSCs 中成骨受损。此外，抑制 mTOR 诱导的自噬改善了 O-JBSCs 的衰老表型。使用化学自噬激活剂激活 LepR-Cre+/JBSCs 中的自噬减少了 O 小鼠的肺泡骨吸收。因此，我们的研究表明，ATG 分子和通路在颚骨衰老中至关重要，为理解与年龄相关的颌骨损失提供了新的方法。