Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth. To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters. We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.

中文翻译：

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命运图谱和功能解剖揭示了 I 型干扰素信号对小鼠大脑衰老的危险影响


衰老显着增加患神经退行性疾病的风险。神经炎症是神经退行性疾病以及正常大脑衰老的普遍标志。与年龄相关的神经炎症的哪些分支，以及它们如何使大脑发生病理进展，仍不清楚。老年大脑中存在 I 型干扰素 (IFN-I) 升高的情况已被记录，但其在促进退行性过程（例如脆弱区域神经元损失）中的作用尚未得到深入研究。为了了解衰老大脑中 IFN-I 活性的范围，我们调查了多个年龄段的 IFN-I 反应报告小鼠。我们还检查了小胶质细胞中选择性消融 Ifnar1 的 5 个月和 24 个月大的小鼠，以使用大量 RNA 测序和组织学参数观察在衰老过程中操纵该通路的效果。我们在不同区域的多种脑细胞类型中检测到年龄依赖性的 IFN-I 信号增强，尤其是在小胶质细胞中。选择性去除老年小鼠小胶质细胞中的 Ifnar1 显着降低了大脑整体 IFN-I 特征，抑制了小胶质细胞反应性，减少了神经元损失，恢复了关键神经元基因和通路的表达，并减少了脂褐质的积累，脂褐质是细胞衰老的核心标志。脑。总体而言，我们的研究证明了正常小鼠大脑衰老过程中普遍存在的 IFN-I 活性，并揭示了小胶质细胞 IFN-I 信号在持续神经炎症、神经元功能障碍和分子聚集中发挥的致病性、促退行性作用。 这些发现扩展了对大脑中与年龄相关的炎症主轴（可能与多种神经系统疾病共有）的理解，并为调节异常免疫激活以减轻各个阶段的神经退行性过程提供了理论基础。