拉斯衍生的细胞外基质碎片通过先天性免疫激活驱动衰老
Junzhi Yi1,2, Yixuan Wang1,2, Hairu Sui1,2
1Department of Sports Medicine of the Second Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Nature aging
|September 30, 2025
概括
退化的细胞外基质碎片,特别是来自弹性质的,通过激活免疫细胞并引起炎症来驱动衰老. 抑制NEU1显著延长寿命,并改善老化表型在老鼠和猪.
科学领域:
- 生物遗传学 生物遗传学
- 免疫学 免疫学 免疫学
- 细胞外矩阵生物学 细胞外矩阵生物学
背景情况:
- 细胞在衰老中的作用已得到充分研究,但细胞外基质 (ECM) 和其降解对衰老的影响在很大程度上仍未被探索.
- 系统衰老涉及复杂的分子和细胞变化,循环因素的潜在贡献.
- 衰老过程与改变的组织组成和功能有关,包括ECM的变化.
研究的目的:
- 为了研究细胞外矩阵碎片在系统衰老中的作用.
- 为了识别与年龄相关且影响寿命的特定ECM衍生碎片.
- 阐明ECM碎片影响衰老的分子机制,并探索治疗干预措施.
主要方法:
- 从弹性素,氨酸和纤维菌素中对与年龄相关的碎片进行血清分析.
- 在暴露于弹性素衍生碎片的小鼠中进行寿命研究.
- 人类队列研究将碎片水平与衰老指标相关联 (n=1,068).
- 涉及NEU1 (神经氨基酶1) 和单细胞/巨细胞激活的机制研究.
- 使用NEU1抑制剂治疗老年小鼠,免疫人性化小鼠和猪的治疗干预.
主要成果:
- 弹性素,氨酸和纤维生素衍生碎片的血清水平随着年龄的增长而增加.
- 拉斯衍生碎片在小鼠中显示出最强的寿命缩短效果,与人类的衰老指标相关.
- 来自弹性质碎片的VGVAPG寡 (E-动机) 通过NEU1激活单细胞/巨细胞,诱导炎症.
- 抑制NEU1在老年小鼠中延长了长达17%的寿命,并改善了物种间的衰老表型.
结论:
- 退化的细胞外基质碎片,特别是弹性质碎片,充当衰老的循环驱动因素.
- 由弹性质碎片激活的NEU1介导的炎症途径是衰老的一个关键机制.
- 针对NEU1代表了一种有前途的治疗策略,用于打击衰老和与年龄相关的疾病.
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