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role of SIRT1 in normal function under both ad lib and calorie restricted conditions conceals the potential pro-oxidative damage role of SIRT1. The normal survival in the SIRT1 +/- mice suggests that a reduction of SIRT1 expression does not reduce the life span but also does not extend it.
Figure 22. Reduced life span of SIRT1 knockout mice under ad-lib and calorie restriction conditions
(A) Survival curves for SIRT1 +/+ (n=16), +/- (n=15), -/- mice (n=14) on ad-lib diet. P < 0.05, log-rank test. (B) Survival curves for SIRT1 +/+ (n= 13), +/- (n=18), -/- (n=12) mice on 40% reduced calorie diet. P < 0.001, log-rank test. The mice were 2-5 months old at the onset of calorie restriction.
2.5. Discussion
Sirtuins including Sir2 and SIRT1 have been described as mediators of the effect of calorie restriction on longevity and are widely believed to protect against aging (Cohen et al., 2004; Guarente, 2005a). However, others have proposed that sirtuins are not required for the effects of CR on life span (Hansen et al., 2007; Kaeberlein et al., 2004; Kaeberlein et al., 2006; Lee et al., 2006) and our previous results in yeast suggested that the lack of Sir2 can also increase resistance to stress and extend further the chronological life span of calorie restricted cells or yeast also lacking components of the Ras/cAMP/PKA or Sch9 pathway (Fabrizio et al., 2005; Longo and Kennedy, 2006). In agreement with our results in S. cerevisiae, here we found that inhibition of SIRT1 reduces IGF-I signaling and
54
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 64 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | role of SIRT1 in normal function under both ad lib and calorie restricted conditions conceals the potential pro-oxidative damage role of SIRT1. The normal survival in the SIRT1 +/- mice suggests that a reduction of SIRT1 expression does not reduce the life span but also does not extend it. Figure 22. Reduced life span of SIRT1 knockout mice under ad-lib and calorie restriction conditions (A) Survival curves for SIRT1 +/+ (n=16), +/- (n=15), -/- mice (n=14) on ad-lib diet. P < 0.05, log-rank test. (B) Survival curves for SIRT1 +/+ (n= 13), +/- (n=18), -/- (n=12) mice on 40% reduced calorie diet. P < 0.001, log-rank test. The mice were 2-5 months old at the onset of calorie restriction. 2.5. Discussion Sirtuins including Sir2 and SIRT1 have been described as mediators of the effect of calorie restriction on longevity and are widely believed to protect against aging (Cohen et al., 2004; Guarente, 2005a). However, others have proposed that sirtuins are not required for the effects of CR on life span (Hansen et al., 2007; Kaeberlein et al., 2004; Kaeberlein et al., 2006; Lee et al., 2006) and our previous results in yeast suggested that the lack of Sir2 can also increase resistance to stress and extend further the chronological life span of calorie restricted cells or yeast also lacking components of the Ras/cAMP/PKA or Sch9 pathway (Fabrizio et al., 2005; Longo and Kennedy, 2006). In agreement with our results in S. cerevisiae, here we found that inhibition of SIRT1 reduces IGF-I signaling and 54 |
