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The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration

Chen, Danica and Steele, Andrew D. and Hutter, Gregor and Bruno, Joanne and Govindarajan, Arvind and Easlon, Erin and Lin, Su-Ju and Aguzzi, Adriano and Lindquist, Susan and Guarente, Leonard (2008) The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration. Experimental Gerontology, 43 (12). pp. 1086-1093. ISSN 0531-5565.

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A central focus of aging research is to determine how calorie restriction (CR) extends lifespan and delays diseases of aging. SIRT1, the mammalian ortholog of Sir2 in yeast, is a longevity factor which mediates dietary restriction in diverse species. In addition, SIRT1 plays a protective role in several models of neurodegenerative disease. We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. Prion diseases are protein misfolding disorders of the central nervous system with many similarities to other neurodegenerative diseases, including deposition of aggregated protein, gliosis, and loss of synapses and neurons. We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. The expression of PrP mRNA and protein is reduced in the brains of CR mice and in SIRT1 knockout mice, suggesting a possible mechanism for the delayed onset of disease, as PrP levels are a critical determinant of how quickly mice succumb to prion disease. Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. Taken together, our results suggest a more complex interplay between CR, SIRT1, and neurodegenerative diseases than previously appreciated.

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Additional Information:Copyright © 2008 Elsevier. Received 4 July 2008; revised 20 August 2008; accepted 21 August 2008. Available online 30 August 2008. We are grateful to Artur Topolszki and Walker Jackson (WIBR) for assistance with prion inoculations and to Vilma Martins (Ludwig Institute for Cancer Research) for providing the luciferase reporter construct. S.L. is an investigator in the Howard Hughes Medical Institute, D.C. was supported by a Leukemia and Lymphoma Society postdoctoral fellowship (5168-06) and L.G. is funded by the NIH. Appendix A. Supplementary data: Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.exger.2008.08.050.
Funding AgencyGrant Number
Howard Hughes Medical InstituteUNSPECIFIED
Leukemia and Lymphoma Society5168-06
National Institutes of HealthUNSPECIFIED
Subject Keywords:Sirtuin; Aging; Dietary restriction; Amyloid; Transmissible spongiform encephalopathy
Issue or Number:12
Record Number:CaltechAUTHORS:CHEeg08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13063
Deposited By: Archive Administrator
Deposited On:16 Jan 2009 20:56
Last Modified:03 Oct 2019 00:34

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