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Title: GROWTH HORMONE ALTERS COMPONENTS OF THE GLUTATHIONE METABOLIC PATHWAY IN AMES DWARF MICE

Author
item BROWN-BORG, HOLLY - UNIV NORTH DAKOTA
item RAKOCZY, SHARLENE - UNIV NORTH DAKOTA
item Uthus, Eric

Submitted to: Annals of the New York Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/10/2003
Publication Date: 6/1/2004
Citation: Brown-Borg, H.M., Rakoczy, S.G., Uthus, E.O. 2004. Growth hormone alters components of the glutathione metabolic pathway in Ames dwarf mice. Annals of the New York Academy of Sciences. 1019:317-320.

Interpretive Summary: Animals that lack growth hormone (GH) and another growth factor called IGF-1, usually live longer than animals that have normal amounts of these compounds. One animal that lacks these compounds (because of a genetic mutation) is the Ames dwarf mouse. The Ames dwarf mouse lives 50-64% longer than its "normal" counterpart. One possible reason that the Ames dwarf mouse lives so long is that it appears to have an enhanced capacity to neutralize the effects of oxidative damage. We wanted to know if the enhanced oxidative defense system in the Ames dwarf mouse was the result of its lack of GH. Thus, we administered GH to a group of the dwarf mice and compared their oxidative defense system to other dwarf mice that were injected with saline only. We found that the ability to defend against oxidative stress of those mice injected with GH was not as great as that found in the dwarf mice injected with only saline. Our results suggest that this up-regulation of oxidative defenses in the Ames dwarf (as a result of lack of GH) is a factor in the long life of these mice.

Technical Abstract: Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1(IGF-1)/insulin pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF-1 deficient and live 50-64% longer than wild-type littermates (males and females, respectively). Previously, we have shown that Ames mice exhibit elevated levels of antioxidative enzymes and lower oxidative damage. To further explore the relationship between GH and antioxidant expression, we administered GH or saline to dwarf mice and evaluated components of the glutathione (GSH) synthesis and degradation system. Growth hormone treatment significantly elevated kidney gamma-glutamyl-cysteine synthetase protein levels in 3- and 12-month-old dwarf mice. In contrast, the activity of the GSH degradation enzyme, gamma-glutamyl transpeptidase, was suppressed by GH administration in brain (P<.05), kidney (P<0.1), heart (P<.005), and liver (P<.06). Activity levels of the detoxification enzyme, glutathione-S-transferase, were also suppressed in kidney tissues at 3 and 12 months of age and in 12-month-old dwarf liver tissues (P<.05). Taken together, the current results along with data from previous studies support a role for growth hormone in the regulation of antioxidative defense and, ultimately, life span in organisms with altered GH or IGF-1 signaling.