IMPE Abstracts

In this talk I will describe several effects of Growth Hormone (GH) on mammalian growth and aging. Much of the data is derived from two dwarf and one giant strain of mice produced in our laboratory that possess very different degrees of healthy/unhealthy aging. One of the dwarf lines contains a disruption of the GH receptor and binding protein gene (GHR/BP) [PNAS, 94:13215-13220, 1997]. Homozygous GHR/B P"knockout" mice (GHR-/-) show severe postnatal growth retardation, absence of the GHR and GHBP, low levels of serum IGF-I and IGFBP-3, and elevated levels of GH. These parameters are characteristic of the GH insensitivity phenotype typical of humans with Laron Syndrome (LS). Surprisingly, the life span of the GHR/BP -/- mice is significantly longer than +/- or +/+ littermates. In fact, the Methuselah Prize for the longest-lived laboratory mouse has been awarded to these mice. They also possess near normal levels of serum glucose with very low levels of insulin and are extremely sensitive to insulin’s action. Furthermore, the mice are resistant to diet induced diabetes, glomerulosclerosis and cancer. This resistance to cancer is similar to that reported for LS individuals. We also have generated another dwarf strain of mice in which we expressed a GH receptor antagonist transgene. These mice are dwarf with low levels of IGF-1 and show increased health and lifespan but not as enhanced as that found in GHR-/- mice. Finally, we have produced giant GH transgenic mice that die prematurely of liver, heart, and kidney pathology. A comparison of the endocrine/physiological parameters of these three mouse lines will be shown. These mice are valuable reagents for “dissecting” genes/proteins that are regulated by GH and, therefore, may be involved in aging. Finally, I will discuss several different GHR antagonists that we have recently discovered and will discuss their possible use to promote healthy aging.

Key Learning Points

1. Growth Hormone has ‘direct’ and ‘indirect’ effects on growth and aging.

2. Mouse models of acromegaly and Laron Syndrome have been generated and studied.

3. Growth Hormone action is inversely related to longevity; (increased GH, decreased life span; decreased GH, increased lifespan).

4. Several novel GH receptor antagonists have been generated and are currently being evaluated.