The genetic determinants of longevity in C. elegans
CALS Impact Statement
We use the nematode C. elegans as a model system to investigate how longevity of an organism might be regulated at the molecular level. Our research focuses on elucidating the mechanism whereby insulin signaling affects lifespan in C. elegans, and using a functional genomics approach to globally identify and characterize the genetic determinants important to the C. elegans lifespan. Insulin signaling plays a critical role in metabolism, development, and longevity in diverse species, from nematodes to mammals. We have combined comparative genomics with biochemical and functional assays in C. elegans to identify evolutionarily conserved genes that might be downstream effectors of insulin signaling. We hope the continued characterization of these putative downstream genes will help to elucidate how insulin signaling mediates its diverse biological outputs. We have also used genome-wide RNA-interference screens to comprehensively identify new genes that affect C. elegans longevity. We are currently using genetic and molecular approaches to classify each of these candidate longevity genes into specific pathways. We hope that further functional characterization of these candidate longevity genes will provide a global view of the diverse pathways that might affect organismal lifespan.
Our research aims to elucidate the basic mechanisms of aging. Our research will impact the general aging population around the world.
Our research focuses on the identification and characterization of genetic determinants important for C. elegans longevity. The initial strategy is to have part of the lab centered on the key longevity determinant daf-2/insulin signaling pathway and another part of the lab focused on using RNAi screening to identify new longevity genes. Ji Li, a third year graduate student, has recently shown that ftt-2 (a 14-3-3 homolog in C. elegans) has an important role in regulating daf-16/FOXO, the major transcription factor that lies downstream of daf-2/insulin signaling. We will summarize these findings in a manuscript that will hopefully be submitted early in the spring of 2006. Nicole Liachko, another third year graduate student, has been working on identifying direct target genes of DAF-16. She has had some preliminary success, and we hope that she will be able to make some significant progress in the next year. Regarding RNAi screening, we recently completed a genome-wide RNAi screen for new longevity genes. We have now shifted our attention to selecting a subset of the new genes identified in the screen for further analyses. Yuqing Dong, a postdoctoral fellow in the lab, has made promising progress on characterizing the novel longevity gene hcf-1, which appears to act by forming a complex with two important longevity determinants DAF-16 and SIR-2. This work is exciting because whereas DAF-16 and SIR-2 have long been recognized to be important factors, their modes of action are not clear. HCF-1 may represent a novel regulator for both proteins. We hope to complete this line of investigation and submit a manuscript summarizing the results by summer of 2006. Zoey Ni, another postdoctoral fellow in the lab, has obtained intriguing preliminary results with several additional novel longevity genes identified in the RNAi screen. She will hopefully make some significant progress in the coming year.
Our work is basic research. It is difficult to apply specific values.