This Program Project will test pathways and mechanisms implicated in the control of longevity and metabolic damage, for a range of experimental systems. Shared factors that limit or reduce longevity in a variety of widely divergent taxa should be identifiable by studying comparative metabolism. We will seek common """"""""metabolic fingerprints"""""""" predicting survival in diverse model aging systems, using a single set of powerful diagnostic tools. PROJECT 1 utilizes functional criteria to identify new genetic determinants of longevity and stress resistance in C. elegans, testing the hypothesis that these functions reside in the same genes. These genes will be compared to 14 long-lived mutant strains and two dietary means of life-extension, for effects on respiration and metabolic profiles. PROJECT 2 tests a specific prediction of the same hypothesis, that a known antioxidant system--a subset of GST enzymes highly specialized for removal of lipoperoxidation products should extend longevity and enhance resistance to oxidative stress in both fruit flies and nematodes. PROJCT 3 addresses the central role of neuronal metabolism to aging and life span, by comparing measures of oxidative damage and of metabolic status in rats and mice of varying age, +/- oxidative stress, as a consequence of either of two longevity-altering regimens: caloric restriction or epigenetic modification. PROJECT 4 tests the hypothesis that longevity can be extended through epigenetic alteration of gene expression in the mouse--elicited either by transient modification of the maternal diet or by heterozygous mutation to an essential DNA methyltransferase. PROJECT 5 examines yeast mitochondrial respiratory functions, bioenergetics, and damage, testing whether respiratory control determines generation of reactive oxygen species and yeast longevity, and attempting to modulate life span of yeast, worms, and flies by genetic perturbation of the respiratory state. The METABOLIC ASSESSMENT CORE will measure multiple indicators of metabolic pathways, activity and lifetime output; status of antioxidant defenses; and the steady state and post -stress levels of potentially damaging metabolic byproducts. Thus, in paired comparisons for each system, we will test a key prediction of the metabolic-damage model: expected future survival at any age, depends on the current status of macromolecular damage, plus the rate of accrual of new damage -- which in turn reflects the balance between antioxidant defenses and the metabolic generation of free radicals. By finding metabolic patterns that are indicative of longevity in several model systems, we can determine those most likely to be relevant to human aging and age-dependent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG020641-02
Application #
6706909
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (O2))
Program Officer
Finkelstein, David B
Project Start
2003-02-15
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$1,028,400
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Shmookler Reis, Robert J; Xu, Lulu; Lee, Hoonyong et al. (2011) Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants. Aging (Albany NY) 3:125-47
Ayyadevara, Srinivas; Tazearslan, Cagda?; Bharill, Puneet et al. (2009) Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan. Aging Cell 8:706-25
Shmookler Reis, Robert J; Bharill, Puneet; Tazearslan, Cagdas et al. (2009) Extreme-longevity mutations orchestrate silencing of multiple signaling pathways. Biochim Biophys Acta 1790:1075-83
Ounpraseuth, Songthip; Rafferty, Tonya M; McDonald-Phillips, Rachel E et al. (2009) A method to quantify mouse coat-color proportions. PLoS One 4:e5414
Tazearslan, Cagda?; Ayyadevara, Srinivas; Bharill, Puneet et al. (2009) Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance. PLoS Genet 5:e1000452
Singh, Sharda P; Niemczyk, Maciej; Saini, Deepti et al. (2008) Role of the electrophilic lipid peroxidation product 4-hydroxynonenal in the development and maintenance of obesity in mice. Biochemistry 47:3900-11
Chae, Minho; Shmookler Reis, Robert J; Thaden, John J (2008) An iterative block-shifting approach to retention time alignment that preserves the shape and area of gas chromatography-mass spectrometry peaks. BMC Bioinformatics 9 Suppl 9:S15
Leakey, Tatiana I; Zielinski, Jerzy; Siegfried, Rachel N et al. (2008) A simple algorithm for quantifying DNA methylation levels on multiple independent CpG sites in bisulfite genomic sequencing electropherograms. Nucleic Acids Res 36:e64
Zimniak, Piotr (2008) Detoxification reactions: relevance to aging. Ageing Res Rev 7:281-300
Ayyadevara, Srinivas; Dandapat, Abhijit; Singh, Sharda P et al. (2007) Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal. Mech Ageing Dev 128:196-205

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