The theory of Antagonistic Pleiotropy postulates that aging is a consequence of inverse correlation between age and selection pressure. Under this theory, positive selection of mechanisms with early-life beneficial effects occurs, in spite of late-life detrimental effects. Understanding when and how such mechanisms become detrimental is crucial for understanding the principles directing the evolution of aging and the aging process itself. However, our understanding of the molecular underpinnings of antagonistic pleiotropy is lacking. This award will support investigation of a novel mechanism involving the conserved C. elegans JNK protein homolog KGB-I to provide relevant information about the molecular mechanisms of antagonistic pleiotropy and aging. KGB-1 provides protection against heavy metals and protein folding stress during development but reverses its contribution and becomes detrimental during early adulthood, sensitizing animals to stress and shortening their lifespan. The project seeks to understand what causes the switch in KGB-1's effect and the general implications of the switch for aging. The project aims will be achieved by dissecting, genetically and biochemically, age-dependent interactions of KGB-1. Specific studies will be conducted to: 1) Characterize age-dependent and tissue-specific interactions between KGB-1 and other proteins; 2) Examine contribution of genes induced in a KGB-1-, and age-dependent manner to downstream phenotypes; 3) Identify proteins physically interacting with KGB-1 in different ages to characterize shifts in KGB-1's network of interactions. Mutant, RNAi knock-down animals, or transgenic strains will be used in these studies to examine genetic and physical interactions between KGB-1 and its mediators. Additional strains will be used to characterize tissue specificity in the contribution of KGB-1 to stress-resistance phenotypes and in its interactions with its mediators. The research will provide information on a fundamental feature of the evolution of aging and provide a better understanding of the aging process itself. Undergraduate and graduate students, including individuals from underrepresented groups, will be trained in scientific research, participate in research and scientific meetings, and publish their results during the project. In addition, science enrichment outreach to local elementary schools will be conducted. All microarray data generated as part of the study will be uploaded upon publication to the Gene Expression Omnibus (GEO: www.ncbi.nlm.nih.gov/geo/) database repository. Molecular biology reagents (i.e. plasmids, bacterial clones) generated as part of this work will be available to members of the scientific community upon request. Transgenic C. elegans strains generated by this project will be available immediately after publication to members of the scientific community and will be deposited in the C. elegans Genetics Center at the University of Minnesota (www.cgc.cbs.umn.edu/) for wider distribution. Results will be published in peer-reviewed journals, preferably open access ones, and presented at research conferences.
