application) Several mechanisms that may retard aging have been uncovered through research on dietary restriction (DR). This revised application for a competing renewal of the Program Project """"""""Nutritional Probe of the Aging Process"""""""" utilizes transgenic models to directly test potential anti-aging mechanisms of DR. This represents a novel approach and an essential step to understanding the actions of DR. The over-arching hypothesis of this Program Project is that DR extends longevity by enhancing physiological functions involved in maintenance of cellular protection. These investigators have focused on three protective systems that have shown to be altered markedly by DR and that are also amenable to a more direct examination by transgenic manipulation: (1) repair of DNA damage, (2) metabolic regulation of glucose homeostasis, and (3) the glucocorticoid system. Project 1 will test the hypothesis that DR alters aging by reducing the accumulation of DNA damage/mutations using the DNA polymerase knockout mouse model and developing a transgenic mouse model that shows enhanced DNA repair. Project 2 will test the hypothesis that reduced plasma glucose contributes to the increased longevity of rodents fed a DR- diet using transgenic mice that over express GLUT4 glucose transporter protein. Project 3 will test the hypothesis that elevated plasma glucocorticoid levels play a role in the anti-aging action of DR using the CRH (corticosterone releasing hormone) knockout mouse model to prevent the elevated glucocorticoid surge, which is characteristic of DR. The Program Project also will have four Cores: an Administrative Core (Core A), an Animal Core (Core B), a Pathology Core (Core C), and a Developmental Core (Core D). The Animal and Pathology Cores will play a vital role in the Program Project because they will provide the first survival and pathology data on these transgenic mice when fed either ad libitum or a DR-diet. The Developmental Core will generate and characterize transgenic models that allow temporal control of transgene expression to further test the aforementioned and other potential mechanisms in the next generation of DR research.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-DAG-8 (J3))
Program Officer
Finkelstein, David B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center San Antonio
Other Domestic Higher Education
San Antonio
United States
Zip Code
Han, Eun-Soo; Muller, Florian L; Perez, Viviana I et al. (2008) The in vivo gene expression signature of oxidative stress. Physiol Genomics 34:112-26
McCarter, Roger; Mejia, Walter; Ikeno, Yuji et al. (2007) Plasma glucose and the action of calorie restriction on aging. J Gerontol A Biol Sci Med Sci 62:1059-70
Cabelof, Diane C; Ikeno, Yuji; Nyska, Abraham et al. (2006) Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate. Cancer Res 66:7460-5
Fu, Chunxiao; Hickey, Morgen; Morrison, Melissa et al. (2006) Tissue specific and non-specific changes in gene expression by aging and by early stage CR. Mech Ageing Dev 127:905-16
Sharp, Zelton Dave; Bartke, Andrzej (2005) Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci 60:293-300
Han, Eun-Soo; Hickey, Morgen (2005) Microarray evaluation of dietary restriction. J Nutr 135:1343-6
Street, K A; Xu, G; Hall, K L et al. (2005) Rat synapsin 1 promoter mediated transgene expression in testicular cell types. DNA Cell Biol 24:133-40
Muller, Florian L; Liu, Yuhong; Van Remmen, Holly (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064-73
Chen, Xinlian; Liang, Hanyu; Van Remmen, Holly et al. (2004) Catalase transgenic mice: characterization and sensitivity to oxidative stress. Arch Biochem Biophys 422:197-210
Cook, Peyton; Fu, Chunxiao; Hickey, Morgen et al. (2004) SAS programs for real-time RT-PCR having multiple independent samples. Biotechniques 37:990-5

Showing the most recent 10 out of 33 publications