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biochemical changes resembling those observed in CR rodents and monkeys. In addition, although the participants had a marked reduction in weight, they exhibited excellent health and a high level of physical and mental activity (Walford et al., 2002). It was also reported that in the Japanese people on the island of Okinawa with lower calorie intake than average have lower rates of death due to cerebral vascular disease, malignancy and heart disease (Kagawa, 1978).
Despite the long history of studying CR, how exactly CR delays aging and elongate lifespan remains unclear. CR induces a broad range of physiological changes in tested animals, such as lower body temperature, lower blood glucose and insulin levels, lower level of NADH within cells, higher levels of the adrenal steroid dehydroepiandrosterone sulfate and reduced body fat and weight among others. CR normally reduces the size of some organs except that of brain. In the past few years, several hypotheses have been proposed. One theory proposes that the reduction in protein turnover may result in the accumulation of aberrant proteins and aging and that CR promotes the degradation of proteins for energy metabolism and therefore delays aging (Aksenova et al., 1998). In another theory, CR benefits were related to the reduction of AGE (advanced glycation end products), which represent the covalent modifications of proteins by derivatives of glucose and are linked to age-related pathologies (Cefalu et al., 1995; Lee and Cerami, 1992). Most of the theories have gathered some experimental support but remain controversial. Among them, reduction in oxidative stress in CR is one of the most influential ones (Ingram et al., 2001). Firstly, oxidative damage to proteins (Aksenova et
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 15 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 5 biochemical changes resembling those observed in CR rodents and monkeys. In addition, although the participants had a marked reduction in weight, they exhibited excellent health and a high level of physical and mental activity (Walford et al., 2002). It was also reported that in the Japanese people on the island of Okinawa with lower calorie intake than average have lower rates of death due to cerebral vascular disease, malignancy and heart disease (Kagawa, 1978). Despite the long history of studying CR, how exactly CR delays aging and elongate lifespan remains unclear. CR induces a broad range of physiological changes in tested animals, such as lower body temperature, lower blood glucose and insulin levels, lower level of NADH within cells, higher levels of the adrenal steroid dehydroepiandrosterone sulfate and reduced body fat and weight among others. CR normally reduces the size of some organs except that of brain. In the past few years, several hypotheses have been proposed. One theory proposes that the reduction in protein turnover may result in the accumulation of aberrant proteins and aging and that CR promotes the degradation of proteins for energy metabolism and therefore delays aging (Aksenova et al., 1998). In another theory, CR benefits were related to the reduction of AGE (advanced glycation end products), which represent the covalent modifications of proteins by derivatives of glucose and are linked to age-related pathologies (Cefalu et al., 1995; Lee and Cerami, 1992). Most of the theories have gathered some experimental support but remain controversial. Among them, reduction in oxidative stress in CR is one of the most influential ones (Ingram et al., 2001). Firstly, oxidative damage to proteins (Aksenova et |
