Hütter Eveline, Unterluggauer Hermann, Uberall Florian, Schramek Herbert, Jansen-Dürr Pidder
Institut für Biomedizinische Alternsforschung der Osterreichischen Akademie der Wissenschaften, Rennweg 10, A-6020 Innsbruck, Austria.
Exp Gerontol. 2002 Oct-Nov;37(10-11):1165-74. doi: 10.1016/s0531-5565(02)00136-5.
Replicative senescence of human fibroblasts is a widely used cellular model for human aging. While it is clear that telomere erosion contributes to the development of replicative senescence, it is assumed that additional factors contribute to the senescent phenotype. The free radical theory of aging suggests that oxidative damage is a major cause of aging; furthermore, the expression of activated oncogenes, such as oncogenic Ras, can induce premature senescence in primary cells. The functional relation between the various inducers of senescence is not known. The present study was guided by the hypothesis that constitutive activation of normal, unmutated Ras may contribute to senescence-induced growth arrest in senescent human fibroblasts. When various branches of Ras-dependent signaling were investigated, constitutive activation of the Ras/Raf/MEK/ERK pathway was not observed. To evaluate the role of oxidative stress for the senescent phenotype, we also investigated stress-related protein kinases. While we found no evidence for alterations in the activity of p38, we could detect an increased activity of Jun kinase in senescent fibroblasts. We also found higher levels of reactive oxygen species (ROS) in senescent fibroblasts compared to their younger counterparts. The accumulation of ROS in senescent cells may be related to the constitutive activation of Jun kinase.
人成纤维细胞的复制性衰老 是一种广泛用于研究人类衰老的细胞模型。虽然端粒侵蚀显然会导致复制性衰老的发生，但人们认为还有其他因素导致衰老表型。衰老的自由基理论表明，氧化损伤是衰老的主要原因；此外，激活的癌基因（如致癌性Ras）的表达可诱导原代细胞过早衰老。衰老的各种诱导因素之间的功能关系尚不清楚。本研究基于这样一个假设：正常的、未突变的Ras的组成型激活可能导致衰老的人成纤维细胞中衰老诱导的生长停滞。当研究Ras依赖性信号传导的各个分支时，未观察到Ras/Raf/MEK/ERK途径的组成型激活。为了评估氧化应激对衰老表型的作用，我们还研究了与应激相关的蛋白激酶。虽然我们没有发现p38活性改变的证据，但我们可以检测到衰老成纤维细胞中Jun激酶的活性增加。我们还发现，与年轻的成纤维细胞相比，衰老的成纤维细胞中活性氧（ROS）水平更高。衰老细胞中ROS的积累可能与Jun激酶的组成型激活有关。
