Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.

中文翻译：

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哺乳动物大脑的纵向自噬分析揭示了整个健康老龄化过程中持续的线粒体自噬。


线粒体自噬中和线粒体损伤，从而防止细胞功能障碍和细胞凋亡。线粒体自噬缺陷与年龄相关的神经退行性疾病（如帕金森病和阿尔茨海默病）密切相关。虽然线粒体自噬在短寿命模式生物的整个生命周期中都会减少，但这种下降是否发生在衰老的哺乳动物大脑中仍然未知——这是一个对于理解细胞类型和区域特异性神经退行性易感性具有根本重要性的问题。在这里，我们定义了体内完整衰老小鼠大脑内神经元和非神经元细胞类型的基础线粒体自噬和非自噬的纵向动力学。对从年轻到老年年龄的报告小鼠队列进行定量分析，揭示了不同亚区和细胞群之间线粒体自噬和巨自噬的细胞和组织特异性改变，包括多巴胺能神经元、小脑浦肯野细胞、星形胶质细胞、小胶质细胞和中间神经元。我们还发现，健康衰老的标志是差异酸化溶酶体在几个神经细胞亚群中的动态积累。我们的研究结果反对任何与年龄相关的线粒体自噬活性普遍下降，而是证明了线粒体自噬在整个衰老轨迹中的动态波动，对正在进行的治疗发育具有重要意义。