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Caloric Restriction Modulates Early Events in Insulin Signaling in Liver and Skeletal Muscle of Rat

Authors

  • MIN ZHU,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224, USA
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  • RAFAEL DE CABO,

    1. Laboratory of Experimental Gerontology, Gerontology Research Center, Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224, USA
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  • MARK A. LANE,

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    • a

      Current address: Merck and Co., Inc., RY 34-A576, P.O. Box 2000 Rahway, NJ 07065-0900.

  • DONALD K. INGRAM

    Corresponding author
    1. Laboratory of Experimental Gerontology, Gerontology Research Center, Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224, USA
      Address for correspondence: Donald K. Ingram, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Voice: 410-558-8180; fax: 410-558-8323. doni@vax.grc.nia.nih.gov
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Address for correspondence: Donald K. Ingram, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Voice: 410-558-8180; fax: 410-558-8323. doni@vax.grc.nia.nih.gov

Abstract

Abstract: Mutations that extend life span in C. elegans suggest that the insulin/IGF-1 signaling (IS) pathway may play a key role in retarding aging and extending life span by caloric restriction (CR). To evaluate this hypothesis, male rats were subjected to either AL (ad libitum) or CR (40% from AL) for 2 and 25 months, and then the effects of CR on the early events in the IS pathway in liver and muscle were assessed. The results indicated that aging was accompanied by a significant decline in insulin receptor tyrosine phosphorylation (pY-IR) upon insulin stimulation in both tissues, which was correlated with a significant increase in the activity of protein tyrosine phosphatase 1B (PTP-1B). However, these alterations with age were attenuated by 25CR. Parallel changes observed in liver mRNA of CR rats were upregulated insulin receptor (IR), IGF-1R and IRS-1, but increased expression of IR mRNA was dissociated with the IR protein in 25CR rats. The expression of liver mRNAs involved in lipid metabolism was also analyzed. In contrast to 25AL rats, the expression of mRNAs for PPARs (α, δ, and γ) was significantly increased in 25CR rats. SREBP-1c and fatty acid synthase were reduced, and other genes were increased, including hormone-sensitive lipase and PGC-1 by CR. The data suggest that the normal function of insulin receptor in liver and muscle is required for successful aging. An altered expression of transcription of a number of genes involved in lipid metabolism may also contribute to modulation of the IS pathway by CR.

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