對於人類而言，老化是不可避免的，如何延緩老化已經成為人類努力的目標。了解老化背後的機制和原因，可以幫助我們延緩老化。這篇文章中，使用系統生物學的方法，建立老人和年輕人的蛋白質交互作用網路(PPIN)、基因調控網路(GRN)和表觀遺傳網路，即基因和表觀遺傳網路(GEN)。由外周血單核細胞的資訊，我們可以比較這兩個基因和表觀遺傳網路得到老化的機制。此外，我們也調查老化過程中，女性和男性老化機制的差異。根據主成分分析(PCA)，我們使用主要網路投影(PNP)的方法，得到老人和年輕人的核心基因和表觀遺傳網路。透過比較這兩個網路，交集得到共同核心網路、差集得到特有核心網路。同樣地，女性和男性的共同核心網路和特有核心網路也可以得到。由此網路中，我們可以發現許多基因、miRNA、途徑扮演重要的角色在老化的過程中。此外，我們調查老化過程中性別的差異。根據我們的分析，老人特有核心網路中，FLNB、CDK4和ZNF274被mir-223、let-7d和mir-130a抑制，或FYN、CDK4、MAGED1和ZNF274的甲基化，是為了要彌補MAPK信號途徑、T細胞受體信號傳導途徑與神經營養蛋白信號途徑的失調，和細胞週期與細胞凋亡的故障。女性特有核心網路中，TAOK3和TRAF6被mir-141和mir-373抑制，或MAX、TAOK3和MYD88的甲基化，是為了要彌補MAPK信號途徑與Toll樣受體信號傳導途徑的失調，和免疫系統、細胞增生與代謝的故障。男性特有核心網路中，STMN1和LRRFIP2被mir-210和mir-214抑制，或SMAD4和LEF1的甲基化，無法彌補MAPK信號途徑與Wnt信號途徑的失調，和細胞週期與細胞凋亡的故障，導致癌症。我們的研究提供一個新的觀點來對藥物設計以對抗老化，也了解老化過程中男女機制的差異。

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.

致謝 i
摘要 ii
Abstract iv
Content vi
List of Figures viii
List of Tables x
Introduction 1
Materials and Methods 5
2.1 Overview of the construction process of common and specific core GENs of human aging 5
2.2 Data selection and preprocessing 6
2.3 Selection of protein pool and construction of the candidate GENs for young, elder, old females and old males 7
2.4 The regression model of the GENs for young, elder, old females and old males 7
2.5 Construction of GENs of human aging by system identification method and system order detection method 10
2.6 Constructing the core GENs by PNP method 11
Results 14
3.1 Functional networks and pathway analysis of proteins in the GENs for young, elder, old females and old males 14
3.2 Pathway analysis of core proteins and impact of miRNAs and DNA methylation on the elder specific core GEN 16
3.3 Pathway analysis of core proteins and impact of miRNAs and DNA methylation on the old female specific core GEN 19
3.4 Pathway analysis of core proteins and impact of miRNAs and DNA methylation on the old male specific core GEN 21
Discussion 23
4.1 The roles of miRNA regulation and DNA methylation on human aging mechanism based on the elder specific core GEN 23
4.2 The roles of miRNA regulation and DNA methylation on human gender aging mechanism based on the old female specific core GEN 26
4.3 The roles of miRNA regulation and DNA methylation on human gender aging mechanism based on the old male specific core GEN 29
4.4 The overall mechanism of human aging 32
Conclusion 33
Bibliography 35

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