Kalfalah Faiza, Sobek Stefan, Bornholz Beatrice, Götz-Rösch Christine, Tigges Julia, Fritsche Ellen, Krutmann Jean, Köhrer Karl, Deenen René, Ohse Sebastian, Boerries Melanie, Busch Hauke, Boege Fritz
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Med. Faculty, Düsseldorf, Germany.
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Exp Gerontol. 2014 Aug;56:59-68. doi: 10.1016/j.exger.2014.03.017. Epub 2014 Mar 31.
Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67 years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPARγ-coactivator 1α (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin 1. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under baseline conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity.
外在皮肤老化集中于真皮层，这是一个由细胞外基质和长寿成纤维细胞组成的有丝分裂后组织隔室，容易积累损伤和发生适应不良。衰老的人类成纤维细胞表现出线粒体和细胞核功能障碍，这可能是衰老的原因或结果。我们报告了一项对从20 - 67岁女性供体获取的人类真皮成纤维细胞的系统研究，并在低群体倍增水平下进行体外分析，以排除复制性衰老。根据全基因组阵列数据的基因集富集分析，转录组中最显著的与年龄相关的变化是线粒体基因表达下降。与此一致的是，线粒体含量和细胞增殖随供体年龄下降。这与AMP依赖的蛋白激酶（AMPK）上调、PPARγ共激活因子1α（PGC1A）的mRNA水平增加以及NAD(+)依赖的去乙酰化酶sirtuin 1水平降低有关。在衰老细胞中，PGC1A介导的对AICAR直接刺激AMPK的线粒体生物发生反应未减弱，而对饥饿的不依赖PGC1A的线粒体生物发生反应减弱，并伴有活性氧生成增加。总之，这些观察结果表明不依赖PGC1A的线粒体生物发生随年龄下降，在基线条件下，AMPK/PGC1A轴的上调不足以补偿这种下降，导致线粒体含量减少和残余呼吸能力的还原超载。
