| Summary: | 碩士 === 國立清華大學 === 電機工程學系 === 104 === For human being, aging is inevitable. How to slow down aging has become the target of human endeavor. Understanding the reason and the underlying aging mechanisms can help us retard aging. In this study, applying systems biology approach to construct the protein-protein interaction networks (PPINs), gene regulatory networks (GRNs) and epigenetic networks, i.e. genetic and epigenetic networks (GENs), of elderly individuals and young controls, we could compare these GENs to extract the human aging mechanism by using their corresponding microarray data in peripheral blood mononuclear cells, microRNA (miRNA) data and databases-mining. In addition, we further discuss what are the different mechanisms between old females and old males from peripheral blood mononuclear cells to investigate the core genetic and epigenetic mechanism in the human aging process.
The core GENs of elderly individuals and young controls are obtained by applying principal network projection (PNP) to GENs based on Principal Component Analysis (PCA). Through the comparison between the young and elder core GENs, the common core GEN and specific core GENs are respectively acquired by the intersection and distinction of core proteins, core transcription factors (TFs), core target genes, and core miRNAs in the core GENs. Similarly, the common and specific core GENs of different gender elders are also obtained to investigate the distinctive aging mechanism between old males and old females.
From the common and specific core GENs, we found that some genes, pathways and miRNAs play important roles in the human aging process. Furthermore, we could investigate the molecular mechanisms behind them, and could also get more insight into the gender-specific changes in the human aging process. According to the results of the elder specific core GEN, the three genes, FLNB, CDK4 and ZNF274, are inhibited by mir-223, let-7d and mir-130a, and DNA methylation of FYN, CDK4, MAGED1 and ZNF274 in order to overcome dysregulations of MAPK signaling pathway, T-cell receptor signaling pathway and neurotrophin signaling pathway and dysfunctions of cell cycle and apoptosis. According to the results of the old female specific core GEN, the two genes, TAOK3 and TRAF6, are inhibited by mir-141 and mir-373, and DNA methylation of MAX, TAOK3 and MYD88 in order to overcome dysregulations of MAPK signaling pathway and Toll-like receptor signaling pathway and dysfunctions of immune system, proliferation and metabolism. According to the results of the old male specific core GEN, the two genes, STMN1 and LRRFIP2, are inhibited by mir-210 and mir-214, and DNA methylation of SMAD4 and LEF1 can’t overcome dysregulations of MAPK signaling pathway and Wnt signaling pathway and dysfunctions of cell cycle and apoptosis, resulting in cancer. We concluded that the MAPK signaling pathway plays the most important role in the human aging process. This research not only provides a new view to drug target design against aging but also investigates what are the distinctive mechanisms between old females and old males from peripheral blood mononuclear cells in the human aging process.
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