Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
Institute of Biochemistry, Kiel University, Kiel, Germany.
Gut. 2020 Jun;69(6):1064-1075. doi: 10.1136/gutjnl-2019-318491. Epub 2019 Oct 5.
Failing to properly repair damaged DNA drives the ageing process. Furthermore, age-related inflammation contributes to the manifestation of ageing. Recently, we demonstrated that the efficiency of repair of diethylnitrosamine (DEN)-induced double-strand breaks (DSBs) rapidly declines with age. We therefore hypothesised that with age, the decline in DNA damage repair stems from age-related inflammation.
We used DEN-induced DNA damage in mouse livers and compared the efficiency of their resolution in different ages and following various permutations aimed at manipulating the liver age-related inflammation.
We found that age-related deregulation of innate immunity was linked to altered gut microbiota. Consequently, antibiotic treatment, MyD88 ablation or germ-free mice had reduced cytokine expression and improved DSBs rejoining in 6-month-old mice. In contrast, feeding young mice with a high-fat diet enhanced inflammation and facilitated the decline in DSBs repair. This latter effect was reversed by antibiotic treatment. Kupffer cell replenishment or their inactivation with gadolinium chloride reduced proinflammatory cytokine expression and reversed the decline in DSBs repair. The addition of proinflammatory cytokines ablated DSBs rejoining mediated by macrophage-derived heparin-binding epidermal growth factor-like growth factor.
Taken together, our results reveal a previously unrecognised link between commensal bacteria-induced inflammation that results in age-dependent decline in DNA damage repair. Importantly, the present study support the notion of a cell non-autonomous mechanism for age-related decline in DNA damage repair that is based on the presence of 'inflamm-ageing' cytokines in the tissue microenvironment, rather than an intrinsic cellular deficiency in the DNA repair machinery.
未能正确修复受损的 DNA 会加速衰老过程。此外，与年龄相关的炎症会导致衰老的表现。最近，我们证明了二乙基亚硝胺（DEN）诱导的双链断裂（DSB）的修复效率随年龄的增长而迅速下降。因此，我们假设随着年龄的增长，DNA 损伤修复的下降源于与年龄相关的炎症。
我们使用 DEN 诱导的小鼠肝脏中的 DNA 损伤，并比较了在不同年龄和各种旨在操纵肝脏与年龄相关的炎症的排列方式下，其解决效率。
我们发现，先天免疫的与年龄相关的失调与肠道微生物群的改变有关。因此，抗生素治疗、MyD88 缺失或无菌小鼠减少了细胞因子的表达，并改善了 6 个月大的小鼠中的 DSBs 重连。相比之下，用高脂肪饮食喂养年轻小鼠会增强炎症并促进 DSBs 修复的下降。抗生素治疗可以逆转这种作用。用钆处理补充或失活库普弗细胞可减少促炎细胞因子的表达并逆转 DSBs 修复的下降。添加促炎细胞因子会消除巨噬细胞衍生的肝素结合表皮生长因子样生长因子介导的 DSBs 重连。
总之，我们的研究结果揭示了共生细菌诱导的炎症与 DNA 损伤修复随年龄下降之间以前未被认识的联系。重要的是，本研究支持了基于组织微环境中“炎症衰老”细胞因子存在而非 DNA 修复机制内在细胞缺陷的与年龄相关的 DNA 损伤修复的细胞非自主机制的概念。
