Our long-term goal is to understand the molecular and physiological processes that lead to aging and senescence in the nematode Caenorhabditis elegans. During this renewal period I propose to continue the genetic analysis of the processes specifying """"""""aging"""""""". If we accept the premise that organismic senescence and death result from changes in metabolic and physiological processes that enfeeble the homeostatic mechanisms of the organism, then any mutation that lengthens life must somehow have altered those rate-determining processes normally driving senescence. For this reason, we will isolate and characterize mutants having maximum life spans longer than wild type; we have called the phenotype of such mutants """"""""Age"""""""". Since the original application, we have completed a variety of classical and molecular genetic studies demonstrating that molecular genetic analysis can be fully implemented in the study of aging in C. elegans. During the next five-year period we intend to gain an understanding of the mode of action of age-] at the molecular level and to identify many more of the genes involved in limiting life span. We intend to focus our research over the next five years in four major directions. (1) Cloning of the age-] gene in which we will identify the genomic region specifying age-] and prove its identity by transformation and by sequence analysis of mutant alleles. (2) Molecular characterization of the age-1 gene, where we intend to characterize the age-] transcription pattern. (3) Isolation of and genetic characterization of other Age loci. (4) Genetic and phenotypic characterization of these new Age mutants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG008322-04
Application #
3119903
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1988-08-01
Project End
1995-07-31
Budget Start
1992-09-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Type
Other Domestic Higher Education
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
Rikke, B A; Murakami, S; Johnson, T E (2000) Paralogy and orthology of tyrosine kinases that can extend the life span of Caenorhabditis elegans. Mol Biol Evol 17:671-83
Murakami, S; Tedesco, P M; Cypser, J R et al. (2000) Molecular genetic mechanisms of life span manipulation in Caenorhabditis elegans. Ann N Y Acad Sci 908:40-9
Shook, D R; Johnson, T E (1999) Quantitative trait loci affecting survival and fertility-related traits in Caenorhabditis elegans show genotype-environment interactions, pleiotropy and epistasis. Genetics 153:1233-43
van Swinderen, B; Shook, D R; Ebert, R H et al. (1997) Quantitative trait loci controlling halothane sensitivity in Caenorhabditis elegans. Proc Natl Acad Sci U S A 94:8232-7
Shook, D R; Brooks, A; Johnson, T E (1996) Mapping quantitative trait loci affecting life history traits in the nematode Caenorhabditis elegans. Genetics 142:801-17
Lithgow, G J; White, T M; Melov, S et al. (1995) Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 92:7540-4
Johnson, T E; Tedesco, P M; Lithgow, G J (1993) Comparing mutants, selective breeding, and transgenics in the dissection of aging processes of Caenorhabditis elegans. Genetica 91:65-77
Johnson, T E; Nelson, G A (1991) Caenorhabditis elegans: a model system for space biology studies. Exp Gerontol 26:299-309