Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
R&D Unit, Amorepacific Corporation, 17074 Gyeonggi-do, Republic of Korea.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31535-31546. doi: 10.1073/pnas.1920338117. Epub 2020 Nov 23.
Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.
细胞衰老被定义为细胞增殖的稳定和持久停滞。在这里，我们研究了衰老细胞是否可以失去衰老特征并重新进入细胞周期阻滞（静止）的可逆状态。我们基于先前的实验证据构建了细胞衰老的分子调控网络。为了推断网络的调控逻辑，我们用人正常皮肤成纤维细胞进行了磷酸化蛋白芯片实验，并使用该数据通过进化算法优化分子之间的调控关系。通过对网络模型的集合分析，我们确定了 3-磷酸肌醇依赖性蛋白激酶 1（PDK1）作为抑制剂的有前途的靶点，以将衰老状态转化为静止状态。我们表明，在衰老的人皮肤成纤维细胞中抑制 PDK1 通过抑制核因子κB 和 mTOR 信号通路消除衰老特征并恢复细胞周期进入，从而恢复皮肤再生能力。我们的发现为治疗与衰老细胞积累相关的与年龄相关疾病的潜在治疗策略提供了深入了解。
