Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Molecular Genetics of Aging in C elegans

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Numerous mutations that increase the life span of the nematode Caenorhabditis elegans have been identified. Many of these are evolutionarily conserved. There is a compelling case that increased stress resistance is involved in increased longevity; however, the specific molecular mechanisms underlying this stress resistance are mostly unknown. Also unknown are what type(s) of stress resistance (resistance to oxidative damage, mutations in DNA, refolding of denatured proteins, etc.) are most crucial to increased longevity. It is also unclear to what extent differential tissue-specificity of stress resistance is important for enhanced longevity. The nematode is an efficient system for exploring tissue-specificity during aging because it is short-lived but multicellular, allowing the study of important aspects of metazoan response to stress that cannot be explored in single-celled organisms. We intend to identify necessary effectors, as well as those that are sufficient for mounting a stress response. We propose an integrated set of methods for addressing these issues. Our general hypothesis is that the ability to resist stress is a necessary part of the life-extension mechanism(s) in C. elegans. (We already know that stress-resistance is not sufficient.) We have previously isolated mutants showing altered response to the intracellular superoxide-generating quinone: juglone, and demonstrated that some O2-stress resistant mutants have increased mean and maximal life spans. We will extend these studies both by selecting more stress-resist mutants and by identifying mutants using novel high-throughput strategies. These studies will also address whether these changes are dependent on known regulatory proteins like DAF-16 and will utilize microarray-based studies to complement the mutational and RNAi approaches, as they can identify critical genes and gene products that might be missed by transcription-based analyses (e.g., heat shock factor).

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