Velarde Michael C, Flynn James M, Day Nicholas U, Melov Simon, Campisi Judith
Buck Institute for Research on Aging, Novato, CA 94945, USA.
Aging (Albany NY). 2012 Jan;4(1):3-12. doi: 10.18632/aging.100423.
Cellular senescence arrests the proliferation of mammalian cells at risk for neoplastic transformation, and is also associated with aging. However, the factors that cause cellular senescence during aging are unclear. Excessive reactive oxygen species (ROS) have been shown to cause cellular senescence in culture, and accumulated molecular damage due to mitochondrial ROS has long been thought to drive aging phenotypesin vivo. Here, we test the hypothesis that mitochondrial oxidative stress can promote cellular senescence in vivo and contribute to aging phenotypes in vivo, specifically in the skin. We show that the number of senescent cells, as well as impaired mitochondrial (complex II) activity increase in naturally aged mouse skin. Using a mouse model of genetic Sod2 deficiency, we show that failure to express this important mitochondrial anti-oxidant enzyme also impairs mitochondrial complex II activity, causes nuclear DNA damage, and induces cellular senescence but not apoptosis in the epidermis. Sod2 deficiency also reduced the number of cells and thickness of the epidermis, while increasing terminal differentiation. Our results support the idea that mitochondrial oxidative stress and cellular senescence contribute to aging skin phenotypes in vivo.
细胞衰老会阻止有发生肿瘤转化风险的哺乳动物细胞增殖，并且还与衰老相关。然而，衰老过程中导致细胞衰老的因素尚不清楚。已有研究表明，过量的活性氧（ROS）会在培养中导致细胞衰老，长期以来人们一直认为线粒体ROS积累造成的分子损伤会在体内驱动衰老表型。在此，我们检验以下假设：线粒体氧化应激可在体内促进细胞衰老，并导致体内衰老表型，特别是在皮肤中。我们发现，在自然衰老的小鼠皮肤中，衰老细胞数量以及线粒体（复合体II）活性受损均增加。利用基因Sod2缺陷小鼠模型，我们发现无法表达这种重要的线粒体抗氧化酶也会损害线粒体复合体II活性，导致核DNA损伤，并在表皮中诱导细胞衰老而非凋亡。Sod2缺陷还减少了表皮细胞数量和厚度，同时增加了终末分化。我们的结果支持线粒体氧化应激和细胞衰老在体内导致皮肤衰老表型这一观点。
