In order to increase understanding of the molecular basis of aging and its retardation by caloric restriction (CR), we employed high density oligonucleotide arrays representing 6347 genes to study the aging process of skeletal muscle Science 285:1390, 1999) and two brain regions (Nature Genetics 25:294, 2000). Aging in the brain (neocortex and cerebellum) of C57BL/6 mice resulted in a differential gene expression pattern indicative of an inflammatory response, oxidative stress (OS) and reduced neurotrophic support in both brain regions. CR, which retards aging in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses. Thus, the central hypothesis to be tested is that OS is a major causative factor in brain aging, and underlies the observed changes in gene expression associate with aging. We propose three Specific Aims:
Specific Aim1. Gene expression profiling of the aging brain: temporal patterns of gene expression in control and CR mice. We have previously described the gene expression profile of 5-month (young adult) and 30-month (aged) B6 mice. We propose to extend these studies to determine the patterns of gene expression in the neocortex, hippocampus and cerebellum of male B6 mice over the adult lifespan. Mice will be studied at five-month age intervals starting at 5 months of age and ending at 35 (control mice) to 45 (CR mice) months of age. The main emphasis of this study is to identify common patterns of age-associated changes in multiple brain regions.
Specific Aim 2 : Identification of cell types associated with a subset of selected age-associated changes in gene expression. In situ hybridizations combined with immunohistochemistry will be used to localize specific mRNAs to individual cell types (i.e., neurons, astrocytes, microglia and vascular endothelium).
Specific Aim 3. A genetic test of the role of reactive oxygen species (ROS) in brain aging in mammals. Using newly developed transgenic mice, we propose to determine whether the alterations in gene expression observed with aging, which represent tissue-specific biomarkers of the aging process, can be prevented in either one strain overexpressing MnSOD or another strain overexpressing mitochondrially-targeted catalase and MnSOD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Wise, Bradley C
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University of Wisconsin Madison
Schools of Medicine
United States
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Park, Sang-Kyu; Kim, Kyoungmi; Page, Grier P et al. (2009) Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8:484-95
Oberdoerffer, Philipp; Michan, Shaday; McVay, Michael et al. (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907-18
Barger, Jamie L; Kayo, Tsuyoshi; Vann, James M et al. (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3:e2264
Park, Sang-Kyu; Page, Grier P; Kim, Kyoungmi et al. (2008) alpha- and gamma-Tocopherol prevent age-related transcriptional alterations in the heart and brain of mice. J Nutr 138:1010-8