Date of Award

8-2011

Document Type

Thesis

Degree Name

Master of Science (MS)

Legacy Department

Biological Sciences

Advisor

Dong, Yuqing

Committee Member

Cao , Min

Committee Member

Wei , Yanzhang

Abstract

The programmed aging process, controlled by a complex gene network, exists in all living organisms. In past decades, studies on the model organism, the nematode worm Caenorhabditis elegans (C. elegans), have revealed some highly conserved molecular pathways involved in lifespan regulation. After entering nucleus, DAF-16 cooperates with corresponding cofactors to achieve its specificity and triggers the transcription of certain subsets of its targets. Here we report that a novel DAF-16 co-factor CeHCF (C.elegans Host Cell Factor) mediate lifespan by regulating NAD+-dependent protein deacetylase, SIR-2.1.
Lifespan assay using Cehcf RNAi revealed that the lifespan extension caused by loss of Cehcf could be fully suppressed by loss of sir-2.1. Cehcf RNAi also fails to further extend the lifespan of long-lived SIR-2.1 overexpression mutants in the lifespan assay, which indicates the epistatic relationship between Cehcf and sir-2.1. Furthermore, transgenic animals generated by microinjection with additional copies of Cehcf and sir-2.1 showed a significant shortened lifespan comparing to sir-2.1 overexpression mutants. Thus overexpression of CeHCF could fully suppress the lifespan elongation in the SIR-2.1 overexpression mutants, which suggests CeHCF may negatively regulate SIR-2.1. Moreover, realtime pcr revealed that the transcriptional level of sod-3, a target of DAF-16, is not directly regulated by CeHCF/SIR-2.1, which suggests that CeHCF/SIR-2.1 may function to limit the specificity of DAF-16 rather than simply to regulate transcriptional activity of DAF-16. Overall, this study revealed a novel genetic pathway, CeHCF/SIR-2.1/DAF-16, and further research on this pathway would largely facilitate our understanding of the aging process.

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