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yeast, C. elegans and Drosophila (Fabrizio et al., 2005; Kaeberlein et al., 1999; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001). Though earlier studies showed the anti-aging effect of Sir2 and its function in calorie restriction (CR) in lower eukaryotes, later studies found that Sir2 is not required for CR-induced life span extension in yeast (Kaeberlein et al., 2004) or worms (Hansen et al., 2007; Kaeberlein et al., 2006; Lee et al., 2006). Notably, our lab showed that lack of Sir2 in yeast further extended the lifespan of calorie restricted cells, or long-lived Sch9 (Fabrizio et al., 2005) or of mutants with deficiencies in the Ras/cAMP pathway suggesting that Sir2 can also promote aging (Fabrizio et al., 2005). Sch9 is homologous to both mammalian S6 kinase and Akt. Expression of mammalian Akt was shown to partially rescue defects in yeast lacking SCH9 but a more recent paper suggests that Sch9 may be more similar to S6 kinase because of its pattern of phosphorylation by TORC1 (Urban et al., 2007). Notably both Akt and S6 kinase have been implicated in promoting aging in higher eukaryotes. SIRT1, the mammalian ortholog of yeast Sir2, has been shown to regulate numerous physiological processes including glucose metabolism, DNA repair and apoptosis (Bordone et al., 2006; Cohen et al., 2004; Luo et al., 2001; Moynihan et al., 2005; Rodgers et al., 2005; Sun et al., 2007). In mammalian cells SIRT1 regulates several stress-response factors, such as p53 tumor suppressor (Langley et al., 2002; Vaziri et al., 2001), forkhead transcription factors (Brunet et al., 2004; Motta et al., 2004), and NF-κB (Yeung et al., 2004) yet it remains unclear if/how SIRT1 regulates resistance to oxidative stress. Notably, SIRT1 is expressed at a high level in the brain compared to other organs (Michishita et al., 2005).
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 24 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 14 yeast, C. elegans and Drosophila (Fabrizio et al., 2005; Kaeberlein et al., 1999; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001). Though earlier studies showed the anti-aging effect of Sir2 and its function in calorie restriction (CR) in lower eukaryotes, later studies found that Sir2 is not required for CR-induced life span extension in yeast (Kaeberlein et al., 2004) or worms (Hansen et al., 2007; Kaeberlein et al., 2006; Lee et al., 2006). Notably, our lab showed that lack of Sir2 in yeast further extended the lifespan of calorie restricted cells, or long-lived Sch9 (Fabrizio et al., 2005) or of mutants with deficiencies in the Ras/cAMP pathway suggesting that Sir2 can also promote aging (Fabrizio et al., 2005). Sch9 is homologous to both mammalian S6 kinase and Akt. Expression of mammalian Akt was shown to partially rescue defects in yeast lacking SCH9 but a more recent paper suggests that Sch9 may be more similar to S6 kinase because of its pattern of phosphorylation by TORC1 (Urban et al., 2007). Notably both Akt and S6 kinase have been implicated in promoting aging in higher eukaryotes. SIRT1, the mammalian ortholog of yeast Sir2, has been shown to regulate numerous physiological processes including glucose metabolism, DNA repair and apoptosis (Bordone et al., 2006; Cohen et al., 2004; Luo et al., 2001; Moynihan et al., 2005; Rodgers et al., 2005; Sun et al., 2007). In mammalian cells SIRT1 regulates several stress-response factors, such as p53 tumor suppressor (Langley et al., 2002; Vaziri et al., 2001), forkhead transcription factors (Brunet et al., 2004; Motta et al., 2004), and NF-κB (Yeung et al., 2004) yet it remains unclear if/how SIRT1 regulates resistance to oxidative stress. Notably, SIRT1 is expressed at a high level in the brain compared to other organs (Michishita et al., 2005). |
