The Effects of Altered Growth Hormone Signaling on Murine Metabolism

Growth hormone signaling influences longevity but the mechanism through which decreased GH action extends lifespan in mice is unknown. It is likely that the key to understanding this phenomenon, and the process of aging itself, is to understand the alterations in metabolism caused by decreased GH action. We investigated changes in energy metabolism in long-lived mice, in hope that these findings can suggest means of improving human health and longevity. These studies consisted of three projects. The influence of altered GH signaling on metabolism was tested by monitoring oxygen consumption, respiratory quotient, and heat production. Intriguingly, long-lived mice have increased oxygen consumption, and decreased respiratory quotient; while short lived mice had opposite effects. These data indicate that decreased GH signaling associates with increased metabolism per unit of body weight and may beneficially affect mitochondrial flexibility by increasing the capacity for fat oxidation; while GH excess generally produces opposite metabolic effects. We then hypothesized that the metabolic characteristics observed in young long-lived mice would persist into old age. Further, we investigated whether caloric restriction or every-other-day diet, two life extending feeding regimens, had any interaction with the metabolic phenotype observed in long-lived mice. The results support our hypothesis that the alterations in metabolism observed in young long-lived mice persist into old age. Neither dietary regimen significantly altered oxygen consumption in GHRKO mice, however, every-other-day diet reduced 24-hour oxygen consumption per gram body weight. These experiments showed that GHRKO mice had increased oxygen consumption regardless of age and life extending dietary interventions we placed them on. We hypothesized that increased oxygen consumption in long-lived mice is the result of increased thermogenesis. To test this hypothesis, we measured oxygen consumption in long-lived mice and controls at the standard lab temperature 23°C, and at 30°C, the murine thermoneutral temperature. When the oxygen consumption of long-lived mice was measured at 30°C, the differences between long-lived and normal mice measured at 23°C were abrogated. These data indicate that increased energy utilization for thermogenesis may contribute to extended longevity of these mutants. Collectively, our results provide important insights into the metabolic characteristics of long-lived mice