Early Hormonal Signaling and Longevity: Role of Long-term Alterations in Glucose Homeostasis

Andrzej Bartke, Ph.D. Southern Illinois University School of Medicine Contact Dr. Bartke

We are studying effects of genes and hormones on aging. We have shown that mutant mice with inherited deficiency of several pituitary hormones live much longer than their normal siblings. These mutants, the Ames dwarf mice, maintain their health, learning abilities, and memory until late in life, are less susceptible to cancer, and outlive normal animals by approximately 50%. On the basis of these and other observations, we have proposed that reduced release of growth hormone (GH) from the anterior pituitary can delay aging and prolong life. We suspect that reduced secretion of hormones from the thyroid gland may also contribute to the remarkable longevity of Ames dwarf mice.

In the proposed research we will test the hypothesis that the actions of GH and thyroid hormones during early (pre-pubertal and pubertal) growth are important for determining the rate of aging and the length of life. We will treat young Ames dwarf mice, and young GH-resistant gene knock-out (GHR-KO) mice with GH, a growth factor that mediates many of GH actions, thyroid hormone, or hormonal combinations. We will start these treatments at the age of two weeks, before the mice are weaned, and continue them until the animals will be eight weeks old. We will study physiological characteristics and expression of various genes during the treatment, and after the treatment is stopped, and determine how long these animals will live. We will focus our studies on the regulation of blood glucose levels by insulin and on genes related to insulin signaling, because we believe that reduced secretion of insulin combined with increased sensitivity to its actions is one of the key reasons for prolonged longevity of Ames dwarf mice and GH resistant knock-out mice. We have already shown that in comparison to normal animals, Ames dwarf mice have reduced levels of insulin and glucose. Moreover, injections of insulin to these animals produce greater phosphorylation of molecules involved in insulin action in the liver and greater suppression of plasma glucose levels. We will determine whether exposure to GH, insulin-like growth factor 1, and thyroid hormone during early growth and development influences the release and actions of insulin during adult life and whether alterations in insulin signaling are associated with differences in aging and life span. Enhanced insulin sensitivity is a likely mechanism of extended longevity because it is also observed in animals in which aging is delayed and life prolonged by reducing their food intake. Importantly, this mechanism of delayed aging may have relevance to the human, because an opposite endocrine condition, insulin resistance, is a major risk factor in development of age-related diseases including diabetes, cardio-vascular disease, and cancer.