Inflammaging, characterized by an increase in low-grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age-related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age-associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL-oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of proinflammatory cytokines (TNFα, IL6 and IL-1β), and markers of fibrosis were significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of proinflammatory cytokines relative to young mice. Short term treatment with the necroptosis inhibitor, necrostatin-1s (Nec-1s), reduced necroptosis, markers of M1 macrophages, expression of proinflammatory cytokines, and markers of fibrosis in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD.

中文翻译：

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坏死性凋亡导致衰老肝脏的慢性炎症和纤维化

炎症以低度慢性炎症随年龄增长为特征，是衰老的标志，与各种年龄相关疾病密切相关，包括慢性肝病 (CLD) 和肝细胞癌 (HCC)。因为坏死性凋亡是一种通过释放 DAMP 诱导炎症的细胞死亡途径，我们测试了与年龄相关的坏死性凋亡增加导致衰老肝脏慢性炎症的假设。与年轻小鼠相比，老年小鼠肝脏中 MLKL 和 MLKL 寡聚体的磷酸化、坏死性凋亡标志物以及 RIPK3 和 RIPK1 的磷酸化显着上调，并且这种增加发生在生命的后半段（即，18 个月后年龄）。M1 巨噬细胞的标志物，促炎细胞因子（TNFα、IL6 和 IL-1β）的表达，随着年龄的增长，肝脏中的纤维化和纤维化标志物显着上调，坏死性凋亡的变化与炎症和纤维化的变化平行。从老年小鼠中分离出的肝细胞和肝脏巨噬细胞显示出相对于年轻小鼠而言坏死性凋亡标志物水平升高以及促炎细胞因子的表达增加。用坏死性凋亡抑制剂 necrostatin-1s (Nec-1s) 进行短期治疗，减少坏死性凋亡、M1 巨噬细胞标志物、促炎细胞因子的表达以及老年小鼠肝脏中的纤维化标志物。因此，我们的数据首次显示，肝脏衰老与坏死性凋亡增加有关，而坏死性凋亡导致肝脏慢性炎症，进而导致肝纤维化和可能的 CLD。