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pathway elongate life span in worms, flies and mice, and this life span extension is often accompanied by an increase in stress resistance.
Sir2 was first brought to broad attention by a study showing that it was required for the elongation of CR-induced elongation of replicative life span in yeast. Some follow up studies supported this notion and revealed its function as a NAD-dependent histone deacetylase, which raised hopes for delaying aging with its activators. However, when Sir2 was tested in our laboratory with a yeast model of chronological aging, which more closely resembles mammalian aging, it was shown to have detrimental roles in some conditions partly through regulation of stress resistance to oxidative damage. This called for a more careful analysis of Sir2 functions and in my study I extended the observation to the mammalian system and found that SIRT1 indeed holds a detrimental role in neuronal oxidative stress. In addition, my finding provides further evidence that SIRT1 is functionally related to insulin/IGF-1 signaling pathway, the key regulatory signaling system that determines the longevity.
We first tested the role of SIRT1 in the regulation of resistance to oxidative stress in neurons. Neurons are a suitable system since they have a relatively high metabolic rate and are subject to high levels of oxidative stress. And in addition, as generally non-renewable post-mitotic cells, the oxidative damages will continuously accumulate in these cells. We found that inhibition of SIRT1 using inhibitors or specifically knock down SIRT1 with siRNA increased resistance to hydrogen peroxide or menadione
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 123 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 113 pathway elongate life span in worms, flies and mice, and this life span extension is often accompanied by an increase in stress resistance. Sir2 was first brought to broad attention by a study showing that it was required for the elongation of CR-induced elongation of replicative life span in yeast. Some follow up studies supported this notion and revealed its function as a NAD-dependent histone deacetylase, which raised hopes for delaying aging with its activators. However, when Sir2 was tested in our laboratory with a yeast model of chronological aging, which more closely resembles mammalian aging, it was shown to have detrimental roles in some conditions partly through regulation of stress resistance to oxidative damage. This called for a more careful analysis of Sir2 functions and in my study I extended the observation to the mammalian system and found that SIRT1 indeed holds a detrimental role in neuronal oxidative stress. In addition, my finding provides further evidence that SIRT1 is functionally related to insulin/IGF-1 signaling pathway, the key regulatory signaling system that determines the longevity. We first tested the role of SIRT1 in the regulation of resistance to oxidative stress in neurons. Neurons are a suitable system since they have a relatively high metabolic rate and are subject to high levels of oxidative stress. And in addition, as generally non-renewable post-mitotic cells, the oxidative damages will continuously accumulate in these cells. We found that inhibition of SIRT1 using inhibitors or specifically knock down SIRT1 with siRNA increased resistance to hydrogen peroxide or menadione |
