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.
