Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice

    Authors

    A. Gesing; K. A. Al-Regaiey; A. Bartke;M. M. Masternak

    Comments

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    Abbreviated Journal Title

    Exp. Gerontol.

    Keywords

    Growth hormone; Calorie restriction; Ames dwarf mice; Metabolism; Transcription factors; MAPK signaling; FATAL NEOPLASTIC DISEASES; RECEPTOR KNOCKOUT MICE; GH-TRANSGENIC MICE; INSULIN SENSITIVITY; DELAYED OCCURRENCE; APKC-LAMBDA/IOTA; SKELETAL-MUSCLE; GENE-EXPRESSION; LIFE-SPAN; LONGEVITY; Geriatrics & Gerontology

    Abstract

    Disruption of the growth hormone (GH) axis promotes longevity and delays aging. In contrast, GH overexpression may lead to accelerated aging and shorter life. Calorie restriction (CR) improves insulin sensitivity and may extend lifespan. Long-lived Ames dwarf (df/df) mice have additional extension of longevity when subjected to 30% CR. The aim of the study was to assess effects of CR or GH replacement therapy separately and as a combined (CR + GH) treatment in GH-deficient df/df and normal mice, on selected metabolic parameters (e. g., insulin, glucose, cholesterol), insulin signaling components (e. g., insulin receptor [IR] beta-subunit, phosphorylated form of IR [IR pY1158], protein kinase C zeta/lambda [p-PKC zeta/lambda] and mTOR [p-mTOR]), transcription factor p-CREB, and components of the mitogen-activated protein kinase (MAPK) signaling (p-ERK1/2, p-p38), responsible for cell proliferation, differentiation and survival. CR decreased plasma levels of insulin, glucose, cholesterol and leptin, and increased hepatic IR beta-subunit and IR pY1158 levels as well as IR, IRS-1 and GLUT-2 gene expression compared to ad libitum feeding, showing a significant beneficial diet intervention effect. Moreover, hepatic protein levels of p-PKC zeta/lambda, p-mTOR and p-p38 decreased, and p-CREB increased in CR mice. On the contrary, GH increased levels of glucose, cholesterol and leptin in plasma, and p-mTOR or p-p38 in livers, and decreased plasma adiponectin and hepatic IR beta-subunit compared to saline treatment. There were no GH effects on adiponectin in N mice. Moreover, GH replacement therapy did not affect IR, IRS-1 and GLUT-2 gene expression. GH treatment abolishes the beneficial effects of CR; it may suggest an important role of GH-IGF1 axis in mediating the CR action. Suppressed somatotrophic signaling seems to predominate over GH replacement therapy in the context of the examined parameters and signaling pathways. (C) 2014 Elsevier Inc. All rights reserved.

    Journal Title

    Experimental Gerontology

    Volume

    58

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    219

    Last Page

    229

    WOS Identifier

    WOS:000345406600031

    ISSN

    0531-5565

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