A Dwarf Mouse Model With Decreased GH/IGF-1 Activity That Does Not Experience Life-Span Extension: Potential Impact of Increased Adiposity, Leptin, and Insulin With Advancing Age

Reduced growth hormone (GH) action is associated with extended longevity in many vertebrate species. GH receptor (GHR) null (GHR(-/-)) mice, which have a disruption in the GHR gene, are a well-studied example of mice that are insulin sensitive and long lived yet obese. However, unlike other mouse lines with reduced GH action, GH receptor antagonist (GHA) transgenic mice have reduced GH action yet exhibit a normal, not extended, life span. Understanding why GHA mice do not have extended life span though they share many physiological attributes with GHR(-/-) mice will help provide clues about how GH influences aging. For this study, we examined age-and sex-related changes in body composition, glucose homeostasis, circulating adipokines, and tissue weights in GHA mice and littermate controls. Compared with previous studies with GHR(-/-) mice, GHA mice had more significant increases in fat mass with advancing age. The increased obesity resulted in significant adipokine changes. Euglycemia was maintained in GHA mice; however, hyperinsulinemia developed in older male GHA mice. Overall, GHA mice experience a more substantial, generalized obesity accompanied by altered adipokine levels and glucose homeostasis than GHR(-/-) mice, which becomes more exaggerated with advancing age and which likely contributes to the lack of life-span extension in these mice.