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Gene Expression Patterns in Calorically Restricted Mice: Partial Overlap with Long-Lived Mutant Mice

Department of Pathology (R.A.M., Y.C.), Geriatrics Center (R.A.M., A.T.G.), and Institute of Gerontology (R.A.M., A.T.G.), University of Michigan, Ann Arbor, Michigan 48109; Department of Physiology (K.A.-R., A.B.), Southern Illinois University, Carbondale, Illinois 62901-6512; and Department of Biomedical Sciences (J.J.K.), College of Osteopathic Medicine and Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701

Address all correspondence and requests for reprints to: Richard A. Miller, Room 5316 CCGCB, Box 0940, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0940. E-mail: millerr{at}umich.edu.

To gain insight into the pathways by which caloric restriction (CR) slows aging, gene expression levels were assessed for each of 2352 genes in the livers of 9-month-old CR and control mice. A total of 352 genes were found to be significantly increased or decreased by CR. The distribution of affected genes among functional classes was similar to the distribution of genes within the test set. Surprisingly, a disruption or knockout of the gene for the GH receptor (GHR-KO), which also produces life extension, had a much smaller effect on gene expression, with no more than 10 genes meeting the selection criterion. There was, however, an interaction between the GHR-KO mutation and the CR diet: the effects of CR on gene expression were significantly lower in GHR-KO mice than in control mice. Of the 352 genes altered significantly by CR, 29 had shown a significant and parallel alteration in expression in a previous study of liver gene expression that compared mice of the long-lived Snell dwarf stock (dw/dw) to controls. These 29 genes, altered both by CR and in dwarf mice, provide a list of biochemical features common to both models of delayed aging, and thus merit confirmation and more detailed study.

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