ABSTRACT
Ames dwarf mice live significantly longer than their wild type siblings and exhibit elevated antioxidative defenses and reduced oxidative damage. This study was conducted to determine the levels of components of glutathione (GSH) synthesis, degradation and utilization in dwarf and wild type mice. Glutamate-cysteine ligase protein levels were significantly elevated in dwarf liver at 3 and 24 months of age and muscle tissue at all ages examined. In kidney, activity of gamma-glutamyltranspeptidase (GGT) was decreased 42, 30 and 33% in 3, 12 and 24-month-old dwarf mice compared to wild type mice (P<0.0001). In contrast, GSH-S-transferase (GST) activity was markedly elevated (85, 113 and 53%) in kidneys of 3, 12 and 24-month-old dwarf mice (P<0.0001). GGT activity was higher in hearts of young dwarf and wild type mice while GST activity tended to be greater in dwarf mice. Similar to liver and kidney, brain GGT activity was also lower in dwarf mice (P<0.0001). Results of these experiments coupled with previous data provide a mechanism to partially explain the enhanced resistance to oxidative insult and conceivably, the extended longevity of dwarf mice.
Subject(s)
Aging/metabolism , Glutathione/metabolism , Longevity , Animals , Brain/metabolism , Dwarfism/metabolism , Glutamate-Cysteine Ligase/metabolism , Glutathione Transferase/metabolism , Kidney/metabolism , Liver/metabolism , Mice , Mice, Mutant Strains , Muscle, Skeletal/metabolism , gamma-Glutamyltransferase/metabolismABSTRACT
The physiological decline that occurs with aging is thought to result, in part, from accumulation of oxidative damage produced by reactive oxygen species (ROS) generated during normal metabolism. Two genetic mouse models of aging, the Ames dwarf and growth hormone (GH) transgenic, suggest that hormone levels may play a role in antioxidative defense and aging. To explore this possibility, catalase (CAT), an enzyme involved in elimination of ROS, was evaluated in long-lived dwarf and short-lived transgenic mice. Catalase activity and/or protein was significantly elevated in livers from dwarf mice at 3, 6, 13-15, and 24 months of age when compared to age-matched wild type mice. In contrast, a 50 and 38% reduction (P<0.05) in CAT protein was observed in 3 and 10 to 12 month old GH transgenics respectively, when compared to wild type mice. Kidneys from old dwarf mice exhibited significantly increased CAT activity (22%), protein (16%) and mRNA expression (59%) compared to wild type mice. Conversely, kidneys from GH transgenic mice showed reductions in CAT activity. The results of this study suggest that hormonal status modulates antioxidative mechanisms and that CAT is important in overall defense capacity with respect to lifespan in both decelerated (dwarf) and accelerated (transgenic) mammalian models of aging.
