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. 2006 May 16;103(20):7901-5.
doi: 10.1073/pnas.0600161103. Epub 2006 May 8.

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Michael S Bonkowski  1 , Juliana S Rocha, Michal M Masternak, Khalid A Al Regaiey, Andrzej Bartke
Affiliations

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Michael S Bonkowski et al. Proc Natl Acad Sci U S A. .

Abstract

Reduced intake of nutrients [calorie restriction (CR)] extends longevity in organisms ranging from yeast to mammals. Mutations affecting somatotropic, insulin, or homologous signaling pathways can increase life span in worms, flies, and mice, and there is considerable evidence that reduced secretion of insulin-like growth factor I and insulin are among the mechanisms that mediate the effects of CR on aging and longevity in mammals. In the present study, mice with targeted disruption of the growth hormone (GH) receptor [GH receptor/GH-binding protein knockout (GHRKO) mice] and their normal siblings were fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age. In normal females and males, CR produced the expected increases in overall, average, median, and maximal life span. Longevity of normal mice subjected to CR resembles that of GHRKO animals fed AL. In sharp contrast to its effects in normal mice, CR failed to increase overall, median, or average life span in GHRKO mice and increased maximal life span only in females. In a separate group of animals, CR for 1 year improved insulin sensitivity in normal mice but failed to further enhance the remarkable insulin sensitivity in GHRKO mutants. These data imply that somatotropic signaling is critically important not only in the control of aging and longevity under conditions of unlimited food supply but also in mediating the effects of CR on life span. The present findings also support the notion that enhanced sensitivity to insulin plays a prominent role in the actions of CR and GH resistance on longevity.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Time course of changes in body weight for male and female normal and GHRKO mice that were fed AL or subjected to 30% CR. Animals were weighed weekly starting at 2 months of age.
Fig. 2.
Fig. 2.
Kaplan–Meier survival plot of normal and GHRKO mice that were fed AL or subjected to 30% CR starting at 2 months of age and maintained for the remainder of life span. Data from males and females are combined.
Fig. 3.
Fig. 3.
Kaplan–Meier survival plot of male normal and GHRKO mice that were fed AL or subjected to 30% CR starting at 2 months of age. CR was maintained throughout the life span.
Fig. 4.
Fig. 4.
Kaplan–Meier survival plot of female normal and GHRKO mice that were fed AL or subjected to 30% CR starting at 2 months of age. CR was maintained throughout the life span.
Fig. 5.
Fig. 5.
Results of ITT in normal and GHRKO mice that were fed AL or subjected to 30% CR between 2 and 12 months of age. All groups were randomly fed (100% AL) overnight. Mice were injected i.p. with insulin (0.75 units/kg of body weight). Glucose was measured in samples collected from the tail vein at specified time points. ∗, P < 0.05 compared with AL controls within phenotype.
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