This proposal is based on the premise that oxygen free radicals are involved in mitochondrial aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondria can lead to damage of macromolecules and result in defective mitochondria. The downward cascade of this process ultimately leads to the state of senescence and the demise of the organism. We hypothesize that factors that can protect the mitochondria from free radical damage have the potential to maintain energy production and tissue function and ultimately to delay the onset of senescence and prolong the lifespan of the organism. Knockout (KO) mice lacking the mitochondrial superoxide metabolizing enzyme, Mn superoxide dismutase (MnSOD), represent an animal model with increased mitochondrial superoxide radicals, accelerated tissue damage, and early demise. We observed a remarkable difference in the mean survival time and the phenotype of the KO mice on different genetic backgrounds. The mean and maximum lifespan difference between the short-lived and the long-lived population is 7 and 5 fold respectively. In addition to the lifespan difference, the long-lived KO mice have a lower level of tissue damage than the short-lived animals. The data indicate that genetic components that cosegregate with the long-lived population have the ability to decelerate tissue damage and consequently, prolong the lifespan. Therefore, identification of these genetic modifiers and understanding their functions protecting mitochondria from superoxide damages may lead to the isolation of genes that can extend lifespan in animal models for human aging. To achieve these goals, the following specific aims are proposed.
Aim I - Fine mapping of the major genetic modifier leading to prolonged lifespan in MnSOD mutant mice.
Aim II - In vivo and in vitro comparison of lifespan and age- related changes between Sod2-/+ and +/+ animals with and without the genetic modifier.
Aim III - Functional studies of the genetic modifier by phenotype analyses of Sod2-/- mice.
Aim I V - Identification of the major modifier gene leading to prolonged lifespan in MnSOD mutant mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016633-04
Application #
6509625
Study Section
Special Emphasis Panel (ZAG1-PKN-2 (J1))
Program Officer
Mccormick, Anna M
Project Start
1999-04-01
Project End
2002-08-31
Budget Start
2002-04-15
Budget End
2002-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$240,427
Indirect Cost
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Erker, Laura; Schubert, Ralf; Elchuri, Sailaja et al. (2006) Effect of the reduction of superoxide dismutase 1 and 2 or treatment with alpha-tocopherol on tumorigenesis in Atm-deficient mice. Free Radic Biol Med 41:590-600
Elchuri, Sailaja; Oberley, Terry D; Qi, Wenbo et al. (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24:367-80
Lynn, Stephen; Huang, Eric J; Elchuri, Sailaja et al. (2005) Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice. Free Radic Biol Med 38:817-28
Limoli, Charles L; Rola, Radoslaw; Giedzinski, Erich et al. (2004) Cell-density-dependent regulation of neural precursor cell function. Proc Natl Acad Sci U S A 101:16052-7
Coling, Donald E; Yu, Kenneth C Y; Somand, David et al. (2003) Effect of SOD1 overexpression on age- and noise-related hearing loss. Free Radic Biol Med 34:873-80
Huang, Ting-Ting; Raineri, Ines; Eggerding, Faye et al. (2002) Transgenic and mutant mice for oxygen free radical studies. Methods Enzymol 349:191-213
Asikainen, Tiina M; Huang, Ting-Ting; Taskinen, Eero et al. (2002) Increased sensitivity of homozygous Sod2 mutant mice to oxygen toxicity. Free Radic Biol Med 32:175-86
Huang, T T; Carlson, E J; Kozy, H M et al. (2001) Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice. Free Radic Biol Med 31:1101-10