The rationale for this grant application grew out of our studies with two knockout mouse models, one deficient in Mn-superoxide reductase (Sod2+A), where we showed that increased generation of reactive oxygen species (ROS) and increased oxidative damage to DNA did not lead to a reduction in life span, while the other model, lacking methionine sulfoxide reductase A (MsrA-/-) and sensitive to hyperoxia, showed increased protein oxidation and a 40% decrease in life span. We believe that these contradictory results are most likely explained by the different type(s) of oxidative damage altered by the two genetic manipulations. The basic underlying premise of this grant application is that not all types of oxidative damage are important in the aging process, but that oxidative damage to protein (most likely specific proteins) is the type of oxidative damage that plays a role in the mechanism underlying aging. Because the effective concentration of methionine is high in proteins and because methionine is easily oxidized, methionine residues in proteins function as a """"""""last chance"""""""" antioxidant defense system for proteins. The cyclic oxidation and the reduction of methionine residues by the methionine sulfoxide reductases inactivate ROS before they oxidize other amino acid residues that are critical to protein function. We hypothesize that oxidative damage to protein is a key mechanism responsible for the reduced life span of the MsrA-/- mice. We propose to test this hypothesis by the following specific aims: 1. To determine if MsrA-/- mice show accelerated aging. 2. To determine if MsrA-/- mice show an increase in oxidative damage to protein in the cytosol and mitochondria, and determine if the increase in oxidative damage has an effect on mitochondrial function. 3. To identify the specific proteins in the cytosol and mitochondria that show increased oxidative damage in tissues of the MsrA-/- mice using novel technologies developed in our laboratory. 4. To rescue the short life span of the MsrA-/- mice and determine if this rescue is associated with reduced oxidative damage to protein.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG026557-05
Application #
7653674
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Velazquez, Jose M
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$231,375
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Styskal, Jennalynn; Nwagwu, Florence A; Watkins, Yvonne N et al. (2013) Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptor function. Free Radic Biol Med 56:123-32
Styskal, Jennalynn; Van Remmen, Holly; Richardson, Arlan et al. (2012) Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models? Free Radic Biol Med 52:46-58
Bokov, Alex F; Garg, Neha; Ikeno, Yuji et al. (2011) Does reduced IGF-1R signaling in Igf1r+/- mice alter aging? PLoS One 6:e26891
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Liang, Hanyu; Yoo, Si-Eun; Na, Ren et al. (2009) Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J Biol Chem 284:30836-44
Bokov, Alex F; Ko, Daijin; Richardson, Arlan (2009) The effect of gonadectomy and estradiol on sensitivity to oxidative stress. Endocr Res 34:43-58
Liang, Hanyu; Ran, Qitao; Jang, Youngmok Charles et al. (2009) Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria. Free Radic Biol Med 47:312-20
Bokov, Alex F; Lindsey, Merry L; Khodr, Christina et al. (2009) Long-lived ames dwarf mice are resistant to chemical stressors. J Gerontol A Biol Sci Med Sci 64:819-27

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