This proposal is based on the premise that oxygen free radicals are involved in mitochondiral aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondda can lead to damage of macromolecules and result in defective mitochondria. 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 iifespan of the organism. MnSOD deficient mice (Sod2-/-) represent an animal model with increased mitochonddal superoxide radicals, accelerated tissue damage, and early demise. We have showed that genetic modifiers play an important role in the determination of the life expectancy of Sod2-/- mice. Thus, Sod2-/- mice on a long-lived genetic background have a lifespan 5 times longer than that of the mutant mice on a short-lived background. We designated the genetic modifiers KOLEGs (KnockOut Life-Extending Genes) and designed a sedes of experiments to map the KOLEG loci and to identify putative modifier genes. To date, we have generated congenic KOLEG-containing mice on an otherwise pure B6 background, mapped the major KOLEG to a 10 cM region, and identified a putative modifier gene in the KOLEG-containing region. The modifier gene encodes the nicotinamide nucleotide transhydrogenase (NNT), which is a membrane-bound protein located in the inner membrane of the Tfitochondria. To build upon our current findings and ultimately identify novel genetic modifiers capable of """"""""nodulating mitochondrial resistance to increased oxidative stress and extending the lifespans of mutant as well as wild type mice, the following specific aims are proposed.
Aim 1 : Identification of additional modifier genes by fine mapping and functional annotation.
Aim 2 : Mechanistic analysis of Nnt as the genetic modifier of Sod2-/-.
Aim 3 : Validation of Nnt as a longevity assurance gene (LAG).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG024400-04
Application #
7260445
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
Program Officer
Mccormick, Anna M
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$323,715
Indirect Cost
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Breyer, Viola; Weigel, Ingrid; Huang, Ting-Ting et al. (2012) Endogenous mitochondrial oxidative stress in MnSOD-deficient mouse embryonic fibroblasts promotes mitochondrial DNA glycation. Free Radic Biol Med 52:1744-9
Corniola, Rikki; Zou, Yani; Leu, David et al. (2012) Paradoxical relationship between Mn superoxide dismutase deficiency and radiation-induced cognitive defects. PLoS One 7:e49367
Liang, Li-Ping; Waldbaum, Simon; Rowley, Shane et al. (2012) Mitochondrial oxidative stress and epilepsy in SOD2 deficient mice: attenuation by a lipophilic metalloporphyrin. Neurobiol Dis 45:1068-76
Raber, Jacob; Villasana, Laura; Rosenberg, Jenna et al. (2011) Irradiation enhances hippocampus-dependent cognition in mice deficient in extracellular superoxide dismutase. Hippocampus 21:72-80
Barreto, George; Huang, Ting-Ting; Giffard, Rona G (2010) Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6 mice. J Neurosurg Anesthesiol 22:214-9
Kim, Aekyong; Joseph, Suman; Khan, Aslam et al. (2010) Enhanced expression of mitochondrial superoxide dismutase leads to prolonged in vivo cell cycle progression and up-regulation of mitochondrial thioredoxin. Free Radic Biol Med 48:1501-12
Kim, Aekyong; Chen, Chih-Hsin; Ursell, Philip et al. (2010) Genetic modifier of mitochondrial superoxide dismutase-deficient mice delays heart failure and prolongs survival. Mamm Genome 21:534-42
Fishman, Kelly; Baure, Jennifer; Zou, Yani et al. (2009) Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD. Free Radic Biol Med 47:1459-67
Zou, Yani; Chen, Chih-Hsin; Fike, John R et al. (2009) A new mouse model for temporal- and tissue-specific control of extracellular superoxide dismutase. Genesis 47:142-54
Rola, Radoslaw; Zou, Yani; Huang, Ting-Ting et al. (2007) Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic Biol Med 42:1133-45;discussion 1131-2

Showing the most recent 10 out of 13 publications