生物老化是一種生物的退化過程。在這過程中，粒線體會出現損傷及功能障礙。芪類化合物如白藜蘆醇和何首烏主要成分二苯乙烯苷過去已被發現能夠幫助促進粒線體活性以及延長模式生物的壽命。然而，白藜蘆醇和二苯乙烯苷如何改善粒線體功能及延長壽命在過去並沒有被徹底探討。在這項研究中，我們研究了二苯乙烯苷對不同階段衰老細胞生理狀況的影響，包括了活性氧物種、粒線體形態和粒線體功能。實驗結果表明，二苯乙烯苷透過幾個途徑促進衰老細胞的功能：（i）通過減少衰老細胞中粒線體超氧化物的形成來減低氧化壓力; （ii）促進粒線體融合，和（iii）提高衰老細胞的粒線體新生成與其呼吸作用。此外，二苯乙烯苷的效果僅表現在衰老細胞。除此之外，在細胞加入二苯乙烯苷的初期，二苯乙烯苷會促使細胞產生更多活性氧物種，這表示二苯乙烯苷對衰老細胞的益處是一種粒線體活性氧誘導適應性效益。

Aging is a degenerative process that exhibits mitochondrial damage and dysfunction. Stilbenes such as resveratrol and THSG have demonstrated to aid mitochondria activities and prolong lifespan in model organisms. How resveratrol and THSG improve mitochondrial function and prolong lifespan is not thoroughly discussed in the past. In this study, we have examined the effects of THSG on different stages of cellular senescence, includes the cellular oxidative stress, mitochondrial morphology, and function. The results demonstrated that THSG promote senescent cell function through several pathways: (i) decrease oxidative stress in the senescent cell by reducing mitochondrial superoxide formation; (ii) promotes mitochondrial fusion, and (iii) improves senescent cell’s mitochondrial biogenesis and cellular respiration. In addition, THSG effects are only present in the senescent cell. Furthermore, THSG act as pro-oxidant during early treatment time, indicating that THSG exerts its benefits by inducing mitochondrial hormesis responses.

ABSTRACT I
ACKNOWLEDGEMENT II
CONTENTS III
Chapter 1 Introduction 1
1.1 Aging is closely related to mitochondria 1
1.2 Mitochondrial respiratory chain is the major site of ROS production 1
1.2.1 The overview of mitochondrial structures and function 1
1.2.2 Oxidative phosphorylation produces ROS 2
1.3 Mitochondrial function is deteriorated with senescent status 4
1.4 The dynamics of mitochondrial morphology is essential for maintaining cellular function 5
1.4.1 The mitochondrial fission machinery 7
1.4.2 The mitochondrial fusion machinery 8
1.4.3 Defects of mitochondrial dynamics led to diseases 9
1.5 Beneficial effects of THSG and Resveratrol 10
1.5.1 Resveratrol mimics effect of calorie restriction 11
1.5.2 Resveratrol and THSG as antioxidant 12
1.6 The Human Umbilical Vein Endothelial Cell (HUVEC) senescence model is chosen in this study 12
1.7 Specific Aim 13
Chapter 2 Materials and Methods 14
2.1 Cell culture and THSG treatment 14
2.2 Detection of apoptotic cells 15
2.3 Cellular oxidative stress detection 15
2.4 Mitochondrial superoxide detection 15
2.5 Cellular superoxide detection 16
2.6 Measurement of mitochondrial membrane potential 16
2.7 Flow cytometry 17
2.8 Immunofluorescence staining 17
2.9 DNA and RNA extraction 17
2.10 Reverse transcriptase 18
2.11 Real-time PCR 19
2.12 Protein expression level detection 20
2.12.1 Protein extraction 20
2.12.2 Western blot analysis 20
2.13 Antibodies 21
Chapter 3 Results 22
3.1 Culturing Human Umbilical Vein Endothelial Cell (HUVEC) to establish senescence model 22
3.2 Resveratrol but not THSG, induced HUVEC apoptosis 22
3.3 THSG reduced cellular oxidative stress in the senescent HUVEC 23
3.4 THSG prevented mitochondrial superoxide production in senescent HUVEC 24
3.4.1 THSG’s protective effects against oxidative stress were not due to the modulation of cellular superoxide 24
3.4.2 Superoxide dismutase gene expression was affected after THSG treatment but did not contribute to the beneficial effects of THSG 25
3.5 THSG affected mitochondrial dynamics 26
3.6 THSG modulated mitochondrial fission and fusion machineries 27
3.7 THSG improved mitochondrial membrane potential in senescent HUVEC 29
3.8 THSG promoted mitochondrial biogenesis in senescent HUVEC 31
3.8.1 THSG increased mitochondrial DNA copy number in senescent HUVEC 31
Chapter 4 Discussion 32
4.1 THSG promotes cellular activities in senescent cells 32
4.2 THSG might exert its beneficial effects by inducing a mitochondrial hormesis response 32
4.3 THSG promotes cellular superoxide formation in senescent cell 34
4.4 Mitochondrial morphology changes are accompanied by the altered mitochondrial function 34
4.5 The expression profile of fission fusion machinery provides hints of the targets of THSG 35
4.6 Conclusions 36
REFERENCES 38
FIGURE LEGEND 45

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