Stöckl Petra, Hütter Eveline, Zwerschke Werner, Jansen-Dürr Pidder
Institute for Biomedical Aging Research, Molecular and Cellular Biology, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
Exp Gerontol. 2006 Jul;41(7):674-82. doi: 10.1016/j.exger.2006.04.009. Epub 2006 May 19.
The mitochondrial theory of aging predicts that functional alterations in mitochondria contribute to the aging process. Whereas this hypothesis implicates increased production of reactive oxygen species (ROS) as a driving force of the aging process, little is known about molecular mechanisms by which mitochondrial impairment might contribute to aging. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between mitochondrial impairment and the appearance of a senescence-like phenotype in young cells. We found that treatment by antimycin A delays proliferation and induces premature senescence in a subset of the cells, associated with increased reactive oxygen species (ROS) production. Quenching of ROS by antioxidants did however not restore proliferation capacity nor prevent premature senescence. Premature senescence is also induced upon chronic exposure to oligomycin, irrespective of ROS production, and oligomycin treatment induced the up-regulation of the cdk inhibitors p16, p21 and p27, which are also up-regulated in replicative senescence. Thus, besides the well-established influence of ROS on proliferation and senescence, a reduction in the level of oxidative phosphorylation is causally related to reduced cell proliferation and the induction of premature senescence.
衰老的线粒体理论预测，线粒体的功能改变会促进衰老过程。尽管这一假说认为活性氧（ROS）生成增加是衰老过程的驱动力，但对于线粒体损伤可能导致衰老的分子机制却知之甚少。我们最近以细胞衰老作为人类衰老的模型，报道了衰老的人类成纤维细胞中呼吸链的部分解偶联。在本通讯中，我们探讨了线粒体损伤与年轻细胞中衰老样表型出现之间潜在的因果关系。我们发现，用抗霉素A处理会延迟细胞增殖，并在一部分细胞中诱导过早衰老，这与活性氧（ROS）生成增加有关。然而，抗氧化剂淬灭ROS并不能恢复增殖能力，也不能防止过早衰老。长期暴露于寡霉素也会诱导过早衰老，而与ROS生成无关，并且寡霉素处理会诱导细胞周期蛋白依赖性激酶（cdk）抑制剂p16、p21和p27上调，这些蛋白在复制性衰老中也会上调。因此，除了ROS对增殖和衰老的既定影响外，氧化磷酸化水平的降低与细胞增殖减少和过早衰老的诱导存在因果关系。
