Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
Aging Cell. 2010 Apr;9(2):291-6. doi: 10.1111/j.1474-9726.2010.00549.x. Epub 2010 Jan 18.
Aging is a multifactorial process where deterioration of body functions is driven by stochastic damage while counteracted by distinct genetically encoded repair systems. To better understand the genetic component of aging, many studies have addressed the gene and protein expression profiles of various aging model systems engaging different organisms from yeast to human. The recently identified small non-coding miRNAs are potent post-transcriptional regulators that can modify the expression of up to several hundred target genes per single miRNA, similar to transcription factors. Increasing evidence shows that miRNAs contribute to the regulation of most if not all important physiological processes, including aging. However, so far the contribution of miRNAs to age-related and senescence-related changes in gene expression remains elusive. To address this question, we have selected four replicative cell aging models including endothelial cells, replicated CD8(+) T cells, renal proximal tubular epithelial cells, and skin fibroblasts. Further included were three organismal aging models including foreskin, mesenchymal stem cells, and CD8(+) T cell populations from old and young donors. Using locked nucleic acid-based miRNA microarrays, we identified four commonly regulated miRNAs, miR-17 down-regulated in all seven; miR-19b and miR-20a, down-regulated in six models; and miR-106a down-regulated in five models. Decrease in these miRNAs correlated with increased transcript levels of some established target genes, especially the cdk inhibitor p21/CDKN1A. These results establish miRNAs as novel markers of cell aging in humans.
衰老是一个多因素的过程，身体功能的退化是由随机损伤驱动的，而由不同的基因编码修复系统来对抗。为了更好地理解衰老的遗传成分，许多研究已经解决了各种衰老模型系统的基因和蛋白质表达谱，这些模型系统涉及从酵母到人类的不同生物体。最近发现的小非编码 miRNAs 是强大的转录后调控因子，每个 miRNA 可以调节多达几百个靶基因的表达，类似于转录因子。越来越多的证据表明，miRNAs 参与了大多数（如果不是全部）重要生理过程的调节，包括衰老。然而，到目前为止，miRNAs 对与年龄相关和与衰老相关的基因表达变化的贡献仍然难以捉摸。为了解决这个问题，我们选择了四个复制细胞衰老模型，包括内皮细胞、复制的 CD8(+) T 细胞、肾近端管状上皮细胞和皮肤成纤维细胞。进一步包括三个机体衰老模型，包括包皮、间充质干细胞和来自老年和年轻供体的 CD8(+) T 细胞群体。使用基于锁核酸的 miRNA 微阵列，我们鉴定了四个常见调节的 miRNAs，miR-17 在所有七个模型中下调；miR-19b 和 miR-20a 在六个模型中下调；miR-106a 在五个模型中下调。这些 miRNA 的减少与一些已建立的靶基因的转录水平增加相关，特别是细胞周期蛋白依赖性激酶抑制剂 p21/CDKN1A。这些结果确立了 miRNAs 作为人类细胞衰老的新标志物。
