MON-480 Reduced Respiration Observed In Isolated Liver Mitochondria Of Long-lived GHR-/- Mice At Early Ages

The relationship between growth hormone (GH) and cellular metabolism is not completely understood, and its effect on mitochondria could play a crucial role in the aging process as implicated by the ‘Mitochondrial Free Radical Theory of Aging’(1). Previous studies on GHR-/- mice with extended lifespans have not focused on cellular metabolism; however, these mice do exhibit enhanced insulin sensitivity and are resistant to diet-induced diabetes. Determining the underlying mechanisms for these shifts in metabolism may prove essential for understanding GH’s influence on aging. In the current study, we isolated mitochondria from livers of male GHR-/- mice at 9, 12, and 24 months of age. Isolated mitochondria were analyzed in vitro using a Seahorse XFe24 Analyzer to measure oxygen consumption rates. Mitochondria from the liver of 9- and 12-month-old GHR-/- mice demonstrate reduced respiration in both the ATP coupled and uncoupled states relative to control littermates; however, this effect is reversed at 24 months of age. Respiratory Control Ratio (RCR) was calculated as declining steadily over the lifespan of WT mice, but this age-related effect was minimal in GHR-/- mice. These results show that changes in insulin sensitivity are not solely responsible for the altered metabolic profiles seen in these mice, and suggests that long-lived GHR-/- mice may maintain healthy mitochondria at relatively older ages despite reduced respiration capacity observed at early ages. 1. Harman, D. The Biologic Clock: The Mitochondria? J. Am. Geriatr. Soc.20, 145-147 (1972).