In this talk I will describe several genes that have been implicated in the action of GH as it relates to aging. Much of the data is derived from two dwarf and one giant strain of mice produced in our laboratory that possess very different life spans. One of the dwarf lines contains a disruption of the GH receptor and binding protein gene (GHR/BP) (PNAS, 94:1321513220, 1997). Homozygous GHR/BP knockout mice (GHR/BP−/−) show severe postnatal growth retardation, absence of the GHR and GHBP mRNA and protein, low levels of serum IGF1 and IGFBP3 and elevated levels of GH. These parameters are characteristic of the GH insensitivity phenotype typical of humans with Laron syndrome. Surprisingly, the life span of the GHR/BP−/− mice is significantly longer than +/− or +/+ littermates. These mice also possess near normal levels of serum glucose with very low levels of insulin and are extremely sensitive to insulins action. Furthermore, the mice are resistant to diabetes-induced glomerulosclerosis. We also have discovered a GH receptor antagonist (A). A brief history of this discovery along with clinical implications will be presented. Expression of the GHA transgene results in another dwarf strain of mice. These mice have low levels of IGF1 but do not possess an increased life expectancy. Additionally, we have produced giant GH transgenic mice that die prematurely of liver, heart and kidney pathology. A comparison of the endocrine parameters of these three mouse lines will be shown. Also, these three strains of mice were found to have very different adipose depot disposition profiles. The interaction of adipose tissue in the aging process will be discussed. Finally, using both genomic and proteomic approaches, we have identified several genes/proteins whose levels change as a function of 1) mouse age, 2) diet induced type 2 diabetes and 3) GH treatment of GH deficient patients.
This work was supported by the State of Ohios Eminent Scholar Program which includes a grant from Milton and Lawrence Goll; WADA; and NIH grants, R15DK075436, RO1 AG19899-05, and P01 AG031736-01A1.