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substrate for the deacetylation activity of SIRT1. This finding further linked SIRT1 function with the key pro-aging system, the insulin/IGF-I pathway. We found that SIRT1 can physically interact with IRS-2, an adaptor protein upstream of Ras in the insulin/IGF-I pathway. SIRT1 inhibition increases acetylation and decreased phosporylation of IRS-2, which in turn leads to reduced Ras/ERK1/2 activation. These data indicate a synergistic relationship between SIRT1 and insulin/IGF-I pathway, in line with yeast findings. Some other studies have also shown that overexpression of SIRT1 in pancreatic beta cells enhances insulin secretion. SIRT1 also represses the expression of PTP1B, a negative regulator of insulin pathway. In addition, SIRT1 depresses the expression of IGF-binding protein 1 (IGFBP1), one of secreted modulators of IGF-I, which may in turn enhance IGF-I function. Hence, our result provides one more link between SIRT1 and the pro-aging insulin/IGF-I signaling pathway.
Intriguingly, although SIRT1 inhibition in neuronal culture and in the brain showed beneficial effects in reducing oxidative damage, deletion of SIRT1 did not result in longer life span. SIRT1 deficient mice displayed severe developmental defects and were short lived under both ad libitum and calorie restricted conditions. These results suggest that the role of SIRT1 deficiency in protecting against oxidative damage may be overridden by the vital importance of this deacetylase in many normal functions. This is consistent with findings in yeast in that SIRT1 can be both anti- and pro-aging depending on the circumstances. Isolating scenarios where SIRT1 exert “harmful” effect from those beneficial ones would be important for understanding aging, the insulin/IGF-I signal
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 125 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 115 substrate for the deacetylation activity of SIRT1. This finding further linked SIRT1 function with the key pro-aging system, the insulin/IGF-I pathway. We found that SIRT1 can physically interact with IRS-2, an adaptor protein upstream of Ras in the insulin/IGF-I pathway. SIRT1 inhibition increases acetylation and decreased phosporylation of IRS-2, which in turn leads to reduced Ras/ERK1/2 activation. These data indicate a synergistic relationship between SIRT1 and insulin/IGF-I pathway, in line with yeast findings. Some other studies have also shown that overexpression of SIRT1 in pancreatic beta cells enhances insulin secretion. SIRT1 also represses the expression of PTP1B, a negative regulator of insulin pathway. In addition, SIRT1 depresses the expression of IGF-binding protein 1 (IGFBP1), one of secreted modulators of IGF-I, which may in turn enhance IGF-I function. Hence, our result provides one more link between SIRT1 and the pro-aging insulin/IGF-I signaling pathway. Intriguingly, although SIRT1 inhibition in neuronal culture and in the brain showed beneficial effects in reducing oxidative damage, deletion of SIRT1 did not result in longer life span. SIRT1 deficient mice displayed severe developmental defects and were short lived under both ad libitum and calorie restricted conditions. These results suggest that the role of SIRT1 deficiency in protecting against oxidative damage may be overridden by the vital importance of this deacetylase in many normal functions. This is consistent with findings in yeast in that SIRT1 can be both anti- and pro-aging depending on the circumstances. Isolating scenarios where SIRT1 exert “harmful” effect from those beneficial ones would be important for understanding aging, the insulin/IGF-I signal |
