The mechanism by which CR works to extend lifespan in multiple rodent species is of high relevance and significance to research into aging. Mitochondria do not seamlessly convert the mitochondrial membrane potential to chemical energy, i.e. ATP. Rather there are several possibilities for proton """"""""leak"""""""" through the mitochondrial inner membrane that do not require passage through the ATPase and synthesis of ATP. The investigator formulates the hypothesis that it is really the rate and extent of these leak reactions that are both 1) major contributors to resting mitochondrial O2 consumption, and 2) major contributors to the production of reactive oxygen species (ROS). Caloric Restriction has been demonstrated consistently to increase lifespan, and to decrease several biochemical endpoints of mitochondrial and oxidative stress specifically in postmitotic tissues. The premise is that Caloric Restriction (CR), hypothyroidism, and modulation of dietary fat will decrease mitochondrial permeability (i.e. proton leak), therefore decreasing molecular Oxygen consumption, and presumably oxidative stress.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG017902-02
Application #
6372462
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Finkelstein, David B
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2001-09-15
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$187,005
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard (2005) Fructose metabolizing enzymes from mouse liver: influence of age and caloric restriction. Biochim Biophys Acta 1721:37-43
Hagopian, Kevork; Harper, Mary-Ellen; Ram, Jesmon J et al. (2005) Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am J Physiol Endocrinol Metab 288:E674-84
Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard (2005) Serine utilization in mouse liver: influence of caloric restriction and aging. FEBS Lett 579:2009-13
Bevilacqua, Lisa; Ramsey, Jon J; Hagopian, Kevork et al. (2005) Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab 289:E429-38
Ramsey, Jon J; Harper, Mary-Ellen; Humble, Stephen J et al. (2005) Influence of mitochondrial membrane fatty acid composition on proton leak and H2O2 production in liver. Comp Biochem Physiol B Biochem Mol Biol 140:99-108
Harper, M-E; Bevilacqua, L; Hagopian, K et al. (2004) Ageing, oxidative stress, and mitochondrial uncoupling. Acta Physiol Scand 182:321-31
Ramsey, Jon J; Hagopian, Kevork; Kenny, Teresa M et al. (2004) Proton leak and hydrogen peroxide production in liver mitochondria from energy-restricted rats. Am J Physiol Endocrinol Metab 286:E31-40
Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard (2004) Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction. Exp Gerontol 39:1145-54
Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard (2003) Caloric restriction increases gluconeogenic and transaminase enzyme activities in mouse liver. Exp Gerontol 38:267-78
Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard (2003) Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice. Exp Gerontol 38:253-66