The long-term objective of this proposal is to delineate mechanisms of the beneficial effects of growth hormone deficiency on mitochondrial bioenergetics. One hypothesis to explain mechanisms of aging proposes that the loss of cellular functions is due to the accumulation of oxidative damage. Mitochondria are the main generators of free radicals and are also the prime targets for consequent oxidative damage. It is thought that genetically-damaged mitochondria accumulate with time and are causally responsible for the aging phenotype via a disturbed energy balance. In recent years, this theory has gained impetus from the discovery of mitochondrial diseases and mtDNA deletions in aged organisms. However, there are still questions regarding the mechanism of the accumulation of these deletions and their physiological relevance. Mice with hereditary dwarfism (Ames dwarf) exhibit growth hormone deficiency, delayed aging, enhanced antioxidant defenses and lower oxidative DNA and protein damage. Absence of GH secretion results in undetectable levels of plasma insulin-like growth factor-1 (IGF-1). Downstream processes of both GH and IGF-1 are therefore not properly targeted. The central hypothesis to be tested is that impaired GH signaling leads to life extension via altered mitochondrial function. Therefore, reduced growth hormone signaling (as that found in dwarf mice) confers a biologic advantage to dwarf mice over wild type mice leading to better enzymatic scavenging of toxic metabolic byproducts, altered mitochondrial bioenergetics and enhanced longevity.
The aims of this proposal are: 1) to determine functional mitochondrial components in Ames dwarf and wild type mice via respiration experiments, protein expression and hydrogen peroxide production; and 2) to determine the activity and expression of enzymes involved in oxidative phosphorylation in vitro and in vivo using GH, IGF-1 or thyroxine replacement. This research will ascertain the function of mitochondria and its potential modulation by reduced GH signaling utilizing dwarf mice and cell culture coupled with biochemical analyses. Determining GH-dependent pathways and mechanisms may suggest potential therapeutic interventions to delay aging, treat aging-related disorders and extend life span in humans.
