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

doi:10.1073/pnas.0600161103

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

Departments of *Internal Medicine–Geriatrics Research,
^†Pharmacology, and
^‡Physiology, Southern Illinois University School of Medicine, Springfield, IL 62794

Edited by Cynthia J. Kenyon, University of California, San Francisco, CA, and approved April 6, 2006 (received for review January 6, 2006)

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.

Footnotes

^§To whom correspondence should be addressed at:
Geriatrics Research, Southern Illinois University, 801 N. Rutledge, P.O. Box 19628, Springfield, IL 62794-9628.
E-mail: abartke{at}siumed.edu
Author contributions: M.S.B. and A.B. designed research; M.S.B., J.S.R., M.M.M., and K.A.A.R. performed research; M.S.B. analyzed data; and M.S.B. and A.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

AL,

ad libitum;

CR,

calorie restriction;

GH,

growth hormone;

GHRKO,

GH receptor/GH-binding protein knockout;

IGF-I,

insulin-like growth factor I;

ITT,

insulin tolerance test.
Freely available online through the PNAS open access option.