Growth Hormone Receptor Gene Disruption in Mature-Adult Mice Improves Glucose Metabolism and Lifespan in Females

Abstract

Growth hormone (GH) serves an important role in early and adult life. Reduction of GH action has been shown to increase life span in many species of animals. In fact, mice bearing a congenital disruption of GH receptor (GHR) gene (GHRKO) hold the record for the longest-lived laboratory mice. In addition to extended life span, these mice show improved health with lower rates of cancer, increased insulin sensitivity, and resistance to age-associated cognitive decline. Furthermore, humans with decreased GH action due to inactivating mutations in the GHR (Laron Syndrome patients) are resistant to cancer and diabetes. Even though the beneficial effects of congenital Ghr gene disruption are well studied, the consequences of postnatal disruption of GH action were unknown. Previously our laboratory generated a mouse line with disrupted GH action at 1.5 months of age (1.5mGHRKO mice). Results showed that these mice had improved insulin sensitivity and increased maximal lifespan only in females, yet growth retardation was still present.To consider decreased GH action as a possible therapeutic to extend healthy lifespan, it was imperative to elucidate the effects of disrupting Ghr gene at a mature-adult age, well after the developmental and growth period of the mice. To this end, we hypothesized that removal of GH action in adult life would convey some of the same health and life span benefits seen in the GHRKO mice without the reduced body length. To test this hypothesis, we used the cre-lox system to generate mice with a disrupted Ghr gene at a mature-adult age (6 months), referred as 6mGHRKO mice. We then performed a phenotypic and lifespan characterization, and tested for molecular mechanisms known to be associated with extended longevity, namely oxidative stress resistance and mTOR modulation. We found that similar to GHRKO and 1.5mGHRKO mice, disruption of GHR at 6 months of age resulted in mice with increased adipose tissue mass, decreased lean mass, high circulating GH, but decreased insulin growth factor-1 levels compared to control mice. Furthermore, the 6mGHRKO mice displayed significantly improved insulin sensitivity in males, with no changes in glucose tolerance. Also, serum levels of inflammatory markers and liver triglycerides were unchanged in these mice. Experiments to evaluate the status of oxidative damage and mTOR activation in liver, skeletal muscle and subcutaneous adipose tissue of male and female 6mGHRKO mice showed a tissue-specificity and sexual dimorphism in these results. Importantly, male and female 6mGHRKO mice showed no change in body length, but mean, median and maximal lifespan were significantly extended in females. In conclusion, disruption of GH action well past sexual maturation produces beneficial effects on insulin sensitivity and aging in mice. Acknowledgements: This work is supported by the State of Ohio’s Eminent Scholar Program, by NIH grant AG059779 and by the AMVETS.