Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Republic of Korea.
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Republic of Korea.
Exp Gerontol. 2018 Jun;106:8-15. doi: 10.1016/j.exger.2018.02.012. Epub 2018 Feb 21.
In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease.
在我们之前的研究中，我们揭示了一种新的机制，即通过抑制 rho 相关蛋白激酶 (ROCK) 来恢复线粒体功能，从而改善亨廷顿舞蹈病综合征 (HGPS) 的表型。然而，这种机制是否也适用于正常衰老细胞的改善仍然难以确定。在这项研究中，我们使用 Y-27632 和法舒地尔作为有效的 ROCK 抑制剂，研究了它们在衰老中的作用。我们发现 ROCK 抑制诱导了线粒体功能的恢复以及代谢重编程，这是正常衰老细胞中改变的两个显著特征。此外，微阵列分析显示，ROCK 抑制上调的途径富集了染色质重塑基因，这些基因可能在缓解与衰老相关的细胞周期停滞中发挥重要作用。事实上，ROCK 抑制诱导了细胞增殖，同时改善了衰老表型。此外，体内实验观察到 ROCK 抑制的恢复作用，这一点可以从促进的皮肤伤口愈合得到证明。总之，我们的数据表明，ROCK 抑制可能被用于改善正常衰老过程和治疗与年龄相关的疾病。
