Growth Hormone Receptor, Calorie Restriction and Longevity in Mice
Growth hormone receptor (GHR)/GH-binding protein knockout (GHRKO) mice are GH resistant. In addition to growth failure and reduced circulating levels of insulin-like growth factor (IGF)-I and insulin, they demonstrate delayed aging and increased life span. 1 Caloric restriction has been shown to further prolong longevity in Ames dwarf mice, but they have multiple anterior pituitary hormone deficiencies due to Prop1 df. Thus, to examine the effect of calorie restriction on purely GH-deficient animals, Bonkowski and colleagues studied GHRKO mice fed either ad lib or a 30% calorie-restricted diet starting at 2 months of age.
Life-long calorie restriction led to decreased body weight in all animals, though the magnitude of the weight reduction in GHRKO vs wild-type (WT) mice was equivalent in males but reduced in females. Fed an ad lib diet, GHRKO mice lived about 200 to 300 days longer than WT mice (mean, median, and maximal longevity; with maximal longevity the mean age at death of the oldest 10% in each group). Calorie restriction modestly increased maximal longevity in GHRKO mice (7.8% vs 17.2% in WT mice), but did not affect mean or median survival (in WT mice, calorie restriction increased median longevity by 25%). The effect of calorie restriction was sexually dimorphic in the GHRKO, but not WT mice. The GHRKO male mice increased median longevity by 1.2% with no change in overall, mean, or maximal longevity from calorie restriction; in females, maximal longevity increased 9% (vs 19% in WT females), but did not affect overall, mean, or median survival. One-year calorie restriction also led to decreased body weight in all animals relative to animals fed ad lib; it also increased insulin sensitivity in the WT mice. The GHRKO mice had enhanced insulin sensitivity relative to WT mice, when both were fed ad lib; there was no further improvement in this with further calorie restriction.
Thus, the GHRKO mouse is an unusual animal model in that calorie restriction did not significantly prolong its lifespan. Possible explanations include a “ceiling effect” in maximal life extension that was already achieved by GHRKO, or a species-specific difference in the optimal severity of calorie restriction that is necessary for prolonging longevity. The authors concluded that the findings more likely indicate the requirement of GHR signaling for lifespan extension by calorie restriction, and attributed this effect to changes in insulin sensitivity.
Bonkowski MS, Rocha JS, Masternak MM, Regaley KA, Bartke A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci U S A. 2006;103:7901–7905.
Both insulin and IGF-I have been implicated in modulating longevity in multiple animal models.2,3 Circulating levels of both hormones are reduced by calorie restriction as well as loss of GHR signaling. The authors here clearly demonstrated the interactive effects of calorie restriction and loss of GHR signaling on insulin sensitivity. Serum IGF-I concentrations in GHRKO mice were about 90% lower than WT mice.1 It would have been interesting if the authors had also measured circulating IGF-I levels at baseline of the insulin-tolerance test to see if calorie restriction further reduced IGF-I levels in the GHRKO mice.
Adda Grimberg , MD
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