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al., 2003; Taguchi et al., 2007). Mutant dwarf mice that have reduced or absent GH, or IGF-1, or high GH but low IGF-1, all have a longer lifespan (Bartke and Brown-Borg, 2004). Overexpression of Klotho, a circulating hormone, extends longevity in mice, possibly through repressing intracellular insulin/IGF-1 signaling (Kurosu et al., 2005).
1.1.3. Calorie restriction and aging
Food restriction was shown to retard growth and elongate lifespan of rodents in 1930s by McCay and colleagues. Further studies indicated that in the components of food, it is the restriction of calorie intake that accounts for the delay of aging (Masoro et al., 1982). The commonly adopted protocol of calorie restriction in rodents is to feed animals with calorie intake of 20–40% less than that consumed ad libitum, without sacrificing micronutrients. The beneficial effects of calorie restriction on lifespan were later expanded to a broad range of species, including yeast, worms, flies and cows (Ingram et al., 2001; Lin et al., 2000). These studies also suggest a conserved mechanism for aging. Not only does CR elongates lifespan, it also delays the appearance of some markers of aging process (Roth et al., 2002) and decreases the occurrence of the age-related diseases, such as Parkinson's disease (Duan and Mattson, 1999) or Alzheimer's disease (Zhu et al., 1999). Some beneficial effects of CR are also exhibited in human subjects. CR was reported to lower human blood glucose, total leukocyte count, cholesterol as well as blood pressure (Walford et al., 1992). The study on humans with 2 year low-calorie consumption in Biosphere2 showed physiological, hematologic, hormonal and
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 14 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 4 al., 2003; Taguchi et al., 2007). Mutant dwarf mice that have reduced or absent GH, or IGF-1, or high GH but low IGF-1, all have a longer lifespan (Bartke and Brown-Borg, 2004). Overexpression of Klotho, a circulating hormone, extends longevity in mice, possibly through repressing intracellular insulin/IGF-1 signaling (Kurosu et al., 2005). 1.1.3. Calorie restriction and aging Food restriction was shown to retard growth and elongate lifespan of rodents in 1930s by McCay and colleagues. Further studies indicated that in the components of food, it is the restriction of calorie intake that accounts for the delay of aging (Masoro et al., 1982). The commonly adopted protocol of calorie restriction in rodents is to feed animals with calorie intake of 20–40% less than that consumed ad libitum, without sacrificing micronutrients. The beneficial effects of calorie restriction on lifespan were later expanded to a broad range of species, including yeast, worms, flies and cows (Ingram et al., 2001; Lin et al., 2000). These studies also suggest a conserved mechanism for aging. Not only does CR elongates lifespan, it also delays the appearance of some markers of aging process (Roth et al., 2002) and decreases the occurrence of the age-related diseases, such as Parkinson's disease (Duan and Mattson, 1999) or Alzheimer's disease (Zhu et al., 1999). Some beneficial effects of CR are also exhibited in human subjects. CR was reported to lower human blood glucose, total leukocyte count, cholesterol as well as blood pressure (Walford et al., 1992). The study on humans with 2 year low-calorie consumption in Biosphere2 showed physiological, hematologic, hormonal and |
