Park Jeongmin, Kim Jin, Chen Yingqing, Song Hyun-Chul, Chen Yubing, Zheng Min, Surh Young-Joon, Kim Uh-Hyun, Park Jeong Woo, Joe Yeonsoo, Chung Hun Taeg
Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea.
Free Radic Res. 2020 Dec;54(11-12):848-858. doi: 10.1080/10715762.2019.1710142. Epub 2020 Mar 31.
Oxidative stress is recognised as a key factor that can lead to cellular senescence and aging. Carbon monoxide (CO) is produced by haemoxygenase-1 (HO-1), which exerts cytoprotective effects in aging-related diseases, whereas the effect of CO on cellular senescence and aging has not been elucidated. In the current study, we clearly demonstrated that CO delays the process of cellular senescence and aging through regulation of miR-34a and Sirt1 expression. CO reduced HO-induced premature senescence in human diploid fibroblast WI-38 cells measured with SA-β-Gal-staining. Furthermore, CO significantly decreased the expression of senescence-associated secretory phenotype (SASP), including TNF-α IL-6, and PAI-1 and increased the transcriptional levels of antioxidant genes, such as HO-1 and NQO1. Moreover, CO apparently enhanced the expression of Sirt1 through down-regulation of miR-34a. Next, to determine whether Sirt1 mediates the inhibitory effect of CO on cellular senescence, we pre-treated WI-38 cells with the Sirt1 inhibitor Ex527 and a miR-34a mimic followed by the administration of HO and evaluated the expression of SASP and antioxidant genes as well as ROS production. According to our results, Sirt1 is crucial for the antiaging and antioxidant effects of CO. Finally, CO prolonged the lifespan of Caenorhabditis and delayed high-fat diet-induced liver aging. Taken together, these findings demonstrate that CO reduces cellular senescence and liver aging through the regulation of miR-34a and Sirt1.
氧化应激被认为是导致细胞衰老和机体老化的关键因素。一氧化碳（CO）由血红素加氧酶-1（HO-1）产生，其在衰老相关疾病中发挥细胞保护作用，而CO对细胞衰老和机体老化的影响尚未阐明。在本研究中，我们明确证明CO通过调节miR-34a和Sirt1的表达来延缓细胞衰老和机体老化的进程。用SA-β-Gal染色法检测发现，CO可减少HO诱导的人二倍体成纤维细胞WI-38细胞过早衰老。此外，CO显著降低衰老相关分泌表型（SASP）的表达，包括肿瘤坏死因子-α、白细胞介素-6和纤溶酶原激活物抑制剂-1，并增加抗氧化基因如HO-1和NQO1的转录水平。此外，CO通过下调miR-34a明显增强了Sirt1的表达。接下来，为了确定Sirt1是否介导CO对细胞衰老的抑制作用，我们先用Sirt1抑制剂Ex527和miR-34a模拟物预处理WI-38细胞，然后给予HO，并评估SASP和抗氧化基因的表达以及活性氧的产生。根据我们的结果，Sirt1对CO的抗衰老和抗氧化作用至关重要。最后，CO延长了秀丽隐杆线虫的寿命，并延缓了高脂饮食诱导的肝脏衰老。综上所述，这些发现表明CO通过调节miR-34a和Sirt1来减少细胞衰老和肝脏衰老。
