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112
Summary and Conclusions
In this dissertation I studied the mechanism of aging, with special attention paid to the central nervous system (CNS). CNS is one of the organs which are most vulnerable to age-related damages and functional decline and is also critical to the control of aging. In this study, I focused on a protein SIRT1, the ortholog of yeast sir2, which was proposed to be an anti-aging factor by some researchers and attracted extensive attention in the last few years. My experiments on the mammalian system, both in vitro and in vivo, indicate multifaceted roles of SIRT1 in neuronal oxidative damage and normal brain functions.
The study of the roles of SIRT1 in neuronal oxidative damage is built on the knowledge about aging accumulated in the last few decades. Some milestone findings revealed (1) oxidative stress as an important mechanism for aging, (2) calorie restriction (CR) as an effective approach for extending life span, and (3) insulin/IGF-I signaling as a key regulatory system for determining longevity. Aging is a complex process and no single theory can yet explain all the causes. Yet several types of evidence supports oxidative stress as a crucial mechanism for aging: oxidative damage increases with age; decreasing oxidative damage delays aging; manipulations that increase life span also reduce the age-related increase in oxidative damage; and oxidative stress contributes to many age-related diseases. CR extends life span in a wide range of organisms, including yeast, worms, fruit flies and mice. However, what mediates the effects of CR is still not clear and more research is needed. Apart from CR, genetic mutations in the insulin/IGF-I signaling
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 122 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 112 Summary and Conclusions In this dissertation I studied the mechanism of aging, with special attention paid to the central nervous system (CNS). CNS is one of the organs which are most vulnerable to age-related damages and functional decline and is also critical to the control of aging. In this study, I focused on a protein SIRT1, the ortholog of yeast sir2, which was proposed to be an anti-aging factor by some researchers and attracted extensive attention in the last few years. My experiments on the mammalian system, both in vitro and in vivo, indicate multifaceted roles of SIRT1 in neuronal oxidative damage and normal brain functions. The study of the roles of SIRT1 in neuronal oxidative damage is built on the knowledge about aging accumulated in the last few decades. Some milestone findings revealed (1) oxidative stress as an important mechanism for aging, (2) calorie restriction (CR) as an effective approach for extending life span, and (3) insulin/IGF-I signaling as a key regulatory system for determining longevity. Aging is a complex process and no single theory can yet explain all the causes. Yet several types of evidence supports oxidative stress as a crucial mechanism for aging: oxidative damage increases with age; decreasing oxidative damage delays aging; manipulations that increase life span also reduce the age-related increase in oxidative damage; and oxidative stress contributes to many age-related diseases. CR extends life span in a wide range of organisms, including yeast, worms, fruit flies and mice. However, what mediates the effects of CR is still not clear and more research is needed. Apart from CR, genetic mutations in the insulin/IGF-I signaling |
