Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Republic of Korea.
Department of Molecular Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
Exp Gerontol. 2019 Oct 15;126:110691. doi: 10.1016/j.exger.2019.110691. Epub 2019 Aug 14.
Senescence is defined as irreversible cell cycle arrest and constitutes a major driving force in diseases related to aging or premature aging. Recent studies indicate that activation of the serine/threonine protein kinase B-raf (BRAF) plays important roles in oncogene-induced senescence. However, it remains elusive whether BRAF inhibition might be effective for abrogating senescence. In this study, we assessed several BRAF inhibitors to identify compounds that ameliorate senescence and revealed SB590885 as an effective agent. Senescence-ameliorating effect upon BRAF inhibition was evident from the observation that SB590885 treatment increased cellular proliferation but diminished senescent phenotypes. Moreover, BRAF inhibition induced the mitochondrial functional recovery along with the metabolic reprogramming, which comprises two salient features that are altered in senescent cells. Furthermore, mitochondrial metabolic reprogramming via BRAF inhibition was a prerequisite for senescence amelioration. Taken together, our data revealed a novel mechanism in which senescence amelioration is mediated by mitochondrial metabolic reprogramming upon BRAF inhibition.
衰老被定义为细胞周期不可逆的停滞，是与衰老或早衰相关疾病的主要驱动力。最近的研究表明，丝氨酸/苏氨酸蛋白激酶 B-raf（BRAF）的激活在癌基因诱导的衰老中发挥重要作用。然而，BRAF 抑制是否能有效消除衰老仍然难以捉摸。在这项研究中，我们评估了几种 BRAF 抑制剂，以确定能改善衰老的化合物，并发现 SB590885 是一种有效的药物。BRAF 抑制后衰老的改善效应明显，因为 SB590885 处理增加了细胞增殖，但减少了衰老表型。此外，BRAF 抑制诱导了线粒体功能的恢复和代谢重编程，这是衰老细胞中改变的两个显著特征。此外，通过 BRAF 抑制进行线粒体代谢重编程是改善衰老的前提。总之，我们的数据揭示了一种新的机制，即通过 BRAF 抑制的线粒体代谢重编程来介导衰老的改善。
