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For example, Alcendor et al reported the beneficial effect of SIRT1 overexpression in the heart against oxidative stress, although they showed that this anti-oxidant effect becomes a pro-oxidant effect at a higher overexpression level (Alcendor RR et al., 2007). Considering SIRT1’s subcellular localization and the many substrates (both inside and outside the nucleus) this is not surprising. In fact, SIRT1 may also play additional important roles in the brain, which could be beneficial. Using SIRT1 knockout mice Boily et al. also showed that SIRT1 is involved in energy metabolism (Boily et al., 2008b).
In agreement with the very different roles of SIRT1, here we show that the pro-oxidative stress role of SIRT1 in neurons and in the mouse brain is not translated into a longer life span. In fact, SIRT1 knockout mice live shorter than wild type controls under both normal and calorie restricted diets. Thus, differently from our studies in yeast, we did not find that calorie restriction extends further the life span of SIRT1 knockout mice, which is consistent with a recent finding by others (Boily et al., 2008b). Considering that SIRT1 +/- mice display a normal mean life span and that SIRT1-/- mice have severe developmental defects including a dwarf phenotype (McBurney et al., 2003), it is likely that these defects are contributing to shortening the life span independently of the rate of aging. This early death does not necessarily contradict our in vitro results especially because the SIRT1+/- mice have a normal life span. Furthermore, our hypothesis is that one of the roles of SIRT1 is to prevent entry into a phase with features of hibernation. The recent results by McBurney and colleagues, showing that calorie restricted SIRT1
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 70 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 60 For example, Alcendor et al reported the beneficial effect of SIRT1 overexpression in the heart against oxidative stress, although they showed that this anti-oxidant effect becomes a pro-oxidant effect at a higher overexpression level (Alcendor RR et al., 2007). Considering SIRT1’s subcellular localization and the many substrates (both inside and outside the nucleus) this is not surprising. In fact, SIRT1 may also play additional important roles in the brain, which could be beneficial. Using SIRT1 knockout mice Boily et al. also showed that SIRT1 is involved in energy metabolism (Boily et al., 2008b). In agreement with the very different roles of SIRT1, here we show that the pro-oxidative stress role of SIRT1 in neurons and in the mouse brain is not translated into a longer life span. In fact, SIRT1 knockout mice live shorter than wild type controls under both normal and calorie restricted diets. Thus, differently from our studies in yeast, we did not find that calorie restriction extends further the life span of SIRT1 knockout mice, which is consistent with a recent finding by others (Boily et al., 2008b). Considering that SIRT1 +/- mice display a normal mean life span and that SIRT1-/- mice have severe developmental defects including a dwarf phenotype (McBurney et al., 2003), it is likely that these defects are contributing to shortening the life span independently of the rate of aging. This early death does not necessarily contradict our in vitro results especially because the SIRT1+/- mice have a normal life span. Furthermore, our hypothesis is that one of the roles of SIRT1 is to prevent entry into a phase with features of hibernation. The recent results by McBurney and colleagues, showing that calorie restricted SIRT1 |
