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 receptor͞GH-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.insulin-like growth factor I ͉ insulin ͉ longevity ͉ aging ͉ dietary restriction M utations affecting somatotropic and͞or insulin signaling can produce a marked increase of longevity in mice. Genes related to homologous signaling pathways in the yeast Saccharomyces cerevisiae, the worm Caenorhabditis elegans, and the f ly Drosophila melanogaster play a key role in the control of aging in these species (1-3). A moderate reduction in the intake of nutrients [also known as calorie restriction (CR)] is extremely effective in delaying aging and increasing longevity in organisms ranging from yeast to mammals (3-5). We have previously reported that CR produces an additional increase in the life span of a long-lived hypopituitary mutant mouse, the Ames dwarf, and alters the slope of its survival curve similarly to the effects of CR in normal mice (6). This result was counterintuitive because both Ames dwarfs and normal animals subjected to CR have reduced insulin-like growth factor I (IGF-I) and insulin levels and share other phenotypic characteristics. Although C. elegans with a mutation in the insulin͞IGF-I homologous signaling pathway Daf 16͞FOXO lived longer when subjected to CR (7,8), CR failed to further increase longevity in D. melanogaster with a chico mutation that interferes with insulin͞IGF-I signaling and prolongs life (9). Interpretation of the findings obtained in Ames dwarf mice is complicated by the fact that in addition to growth hormone (GH...

Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR) is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO) in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15%) CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30%) CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT) in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT) in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.

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