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Title: MITOCHONDRIAL OXIDANT GENERATION AND OXIDATIVE DAMAGE IN AMES DWARF AND GH TRANSGENIC MICE

Author
item BROWN-BORG, HOLLY - UNIV OF NORTH DAKOTA
item Johnson, William
item RAKOCZY, SHARLENE - UNIV OF NORTH DAKOTA
item ROMANICK, MARK - UNIV OF NORTH DAKOTA

Submitted to: American Aging Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/15/2001
Publication Date: 8/1/2001
Citation: Brown-Borg, H., Johnson, W.T., Rakoczy, S., Romanick, M. 2001. Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice. Journal of American Aging Association. 24:85-96.

Interpretive Summary: Mitochondria are cellular components that provide energy for a number of biological processes. To provide this energy, mitochondria utilize most of the oxygen taken up by the cells. Although energy provided by mitochondria is essential for life, some of the oxygen used to create this energy is converted to chemical forms, called reactive oxygen intermediates, that damage the chemical building-blocks of cellular structures. Accumulation o damage caused by reactive oxygen intermediates to proteins, lipids, and DNA of cells contributes to aging and multiple degenerative diseases including cancer, cardiovascular disease, Parkinson's disease, ischemia and chronic inflamation. It was found that mitochondria of mice, whose production of growth hormone is deficient, produce less hydrogen peroxide than normal. Hydrogen peroxide is a reactive oxygen intermediate that can damage cells, but in the mice whose mitochondria produced less hydrogen peroxide as a result of the hormone deficiency, damage to cellular proteins was much les than normal. Mice that are deficient in growth hormone also live longer than normal. Thus, this study shows that mitochondria have an important role in aging and the development of diseases associated with aging and that reduction in cellular damage and extension of life can occur by lowering mitochondrial production of reactive oxygen intermediates.

Technical Abstract: Aging is associated with an accumulation of oxidative damage to proteins, lipids and DNA. Cellular mechanisms designed to prevent oxidative damage decline with aging and in diseases associated with aging. A long-lived mouse, the Ames dwarf, exhibits growth hormone deficiency and heightened antioxidative defenses. In contrast, animals that over express GH have suppressed antioxidative capacity and live half as long as wild type mice. In this study, we examined the generation of H2O2 from liver mitochondria of Ames dwarf and wild type mice and determined the level of oxidative damage to proteins, lipids and DNA in various tissues of these animals. Dwarf liver mitochondria (24 months) produced less H2O2 than normal liver in the presence of succinate (p,0.03) and ADP (p,0.003). Levels of oxidative DNA damage (8OHdG) were variable and dependent on tissue and age in dwarf and normal mice. Forty-seven percent fewer protein carbonyls were detected in 24-month old dwarf liver tissue compared to controls (p,0.04). Forty percent more (p,0.04) protein carbonyls were detected in liver tissue (3-month old) of GH transgenic mice compared to wild types while 12 month old brain tissue had 53% more protein carbonyls compared to controls (p<0.005). Levels of liver malonaldehyde (lipid peroxidation) were not different at 3 and 12 months of age but were greater in Ames dwarf mice at 24 months compared to normal mice. Previous studies indicate a strong negative correlation between plasma GH levels and antioxidative defense. Taken together, these studies show that altered GH-signaling may contribute to differences in the generation of reactive oxygen species, the ability to counter oxidative stress and life span.