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Free radical theory of aging was proposed as early as 1956 (Harman, 1956). Since many ROS, such as peroxides, which are not free radicals, also play a role in oxidative damage to cells, this theory was modified to the oxidative stress theory of aging. During the past few decades evidence has accumulated in support of this theory. Firstly, the level of oxidative damage becomes more apparent with aging. A profound increase of lipid peroxidation (over 20 fold) was shown in aged rats (Roberts and Reckelhoff, 2001). A broad range of proteins are also subjected to oxidative damage during aging, such as mitochondrial aconitase (Yan et al., 1997), glucose-6-phosphate dehydrogenase (Agarwal and Sohal, 1993) and Na+, K+-ATPase (Chakraborty et al., 2003). In addition to lipids and proteins, oxidative damage to DNA has also been observed in aging. By measuring the levels of 8-oxo-2-deoxyguanosine (oxo8dG) in DNA, Hamilton ML et al. showed a marked increase in oxidative modification of nuclear and mitochondrial DNA in aged animals (Hamilton et al., 2001). Secondly, decreasing the generation of ROS or increasing the repair of oxidative damage was shown to delay aging. Selective overexpression of the MSRA gene (methionine sulfoxide reductase A, which catalyzes the repair of oxidized methionine in proteins) in the nervous system markedly extends the lifespan of Drosophila (Ruan et al., 2002). Thirdly, manipulations that increase life span often reduce the age-related increase in oxidative damage. A strain of Drosophila selected for their resistance to paraquat showed extended longevity (Vettraino et al., 2001). Similarly, dwarf mice exhibited an increased life span compared to their wild type littermates and they showed reduced levels of DNA and protein oxidation (Hauck and Bartke, 2001).
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 12 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 2 Free radical theory of aging was proposed as early as 1956 (Harman, 1956). Since many ROS, such as peroxides, which are not free radicals, also play a role in oxidative damage to cells, this theory was modified to the oxidative stress theory of aging. During the past few decades evidence has accumulated in support of this theory. Firstly, the level of oxidative damage becomes more apparent with aging. A profound increase of lipid peroxidation (over 20 fold) was shown in aged rats (Roberts and Reckelhoff, 2001). A broad range of proteins are also subjected to oxidative damage during aging, such as mitochondrial aconitase (Yan et al., 1997), glucose-6-phosphate dehydrogenase (Agarwal and Sohal, 1993) and Na+, K+-ATPase (Chakraborty et al., 2003). In addition to lipids and proteins, oxidative damage to DNA has also been observed in aging. By measuring the levels of 8-oxo-2-deoxyguanosine (oxo8dG) in DNA, Hamilton ML et al. showed a marked increase in oxidative modification of nuclear and mitochondrial DNA in aged animals (Hamilton et al., 2001). Secondly, decreasing the generation of ROS or increasing the repair of oxidative damage was shown to delay aging. Selective overexpression of the MSRA gene (methionine sulfoxide reductase A, which catalyzes the repair of oxidized methionine in proteins) in the nervous system markedly extends the lifespan of Drosophila (Ruan et al., 2002). Thirdly, manipulations that increase life span often reduce the age-related increase in oxidative damage. A strain of Drosophila selected for their resistance to paraquat showed extended longevity (Vettraino et al., 2001). Similarly, dwarf mice exhibited an increased life span compared to their wild type littermates and they showed reduced levels of DNA and protein oxidation (Hauck and Bartke, 2001). |
