PDF(Pubmed)
Abstract：
Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2-/- mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2-/- mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2-/- mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2-/- mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2-/- mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2-/- mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.
摘要：
衰老的特征是氧化增加和细胞保护机制的效率降低。核转录因子-2相关因子(Nrf2)是一种关键的转录因子,控制多种抗氧化蛋白的表达。这里,我们显示Nrf2-/-小鼠表现出年龄依赖性贫血，由于红细胞寿命减少和红细胞生成无效的综合作用，提示Nrf2在衰老过程中在红细胞生物学中的作用。机械上,我们发现抗氧化剂在衰老过程中的表达是由过氧化物酶2激活Nrf2功能介导的。Nrf2的缺乏导致Nrf2-/-小鼠成红细胞中适应性系统的持续氧化和过度激活，例如未折叠蛋白反应（UPR）系统和自噬。由于Nrf2参与自噬相关蛋白如自噬相关蛋白（Atg）4-5和p62的表达，我们发现Nrf2-/-小鼠成红细胞中自噬的晚期受损。UPR系统的过度激活和自噬受损通过caspase-3激活驱动Nrf2-/-小鼠成红细胞的凋亡。作为氧化作用的概念证明，我们用虾青素治疗Nrf2-/-小鼠，抗氧化剂,以负载聚(乳酸-共-乙醇酸)(PLGA)的纳米颗粒(ATS-NP)的形式改善其生物利用度。ATS-NP改善了Nrf2-/-小鼠的年龄依赖性贫血并减少了无效的红细胞生成。总之,我们认为Nrf2在限制与年龄相关的氧化中起关键作用，确保衰老过程中红系成熟和生长。
