Repression of GH signaling: One extended life to live!

have generated two independent dwarf mouse lines with decreased GH action; however, only one has extended longevity. Why? Decreased signaling through the GH/IGF-1 axis in vertebrates, or comparable pathways in invertebrates, has repeatedly been shown to extend lifespan. A prominent example is mice with a disruption in the GH receptor gene (GHR-/-) generated in our laboratory two decades ago [1]. GHR-/-mice are completely resistance to GH action, which causes a reproducible extension of lifespan regardless of the genetic strain of mice [1 ,2] and is officially recognized as the longest-lived laboratory mouse (http://methuselahfoundation.org/). In 1991, our laboratory first described another dwarf mouse line that expresses a growth hormone receptor antagonist (GHA) transgene [3]. The expressed transgene is a mutated bovine GH gene in which the codon for the smaller glycine amino acid at position 119 is replaced with a larger amino acid, which causes steric hindrance when it interacts with the GHR resulting in a classical receptor antagonist [4]. This work ultimately led to the discovery of a pharmaceutical agent, pegvisomant, for the treatment of acromegaly. However, besides providing the basic information for development of this therapeutic, these GHA transgenic mice also provide a novel mouse strain to assess the outcome of a reduction in GH action on health and aging. Noteworthy is the fact that GHA mice do not experience significantly longer lifespans as do other mouse lines with a reduction in the GH/IGF-1 axis, such as the aforementioned GHR-/-mice [2]. As a result, GHA mice have not been as extensively studied. Regardless, comparing the phenotype of GHA mice with other long-lived lines, such as GHR-/-mice, should reveal the most important traits caused by reduced GH action that are responsible for lifespan extension. A summary comparing the phenotypes of GHR-/-and GHA mice is provided in Figure 1. An important distinction between GHA mice and GHR-/-mice is that the GHA does not completely inhibit GH signaling, while inhibition of GH signaling in GHR-/-mice is complete. Thus, we have generated two dwarf mice each with either low or no GH induced intra-Editorial cellular signaling (and each with low levels of IGF-1) yet only one has extended longevity. Again, what molecular mechanisms account for this difference in lifespan between these two dwarf lines? GHA mice generally have a phenotype intermediate between that of control and GHR-/-mice, especially as it relates to size, readouts of the GH/IGF-1 axis and measures of glucose homeostasis. …