Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Arts and Sciences

Department

Biology

First Advisor

Dr. Jim Lund

Abstract

lin-11 and let-711 are early-developmental gene expression regulators with no previously known roles in aging regulation. Yet, they show strong aging-correlated expression profiles (Lund, Tedesco et al. 2002). lin-11 is strongly upregulated in very old worm populations, and let-711 is progressively downregulated in aging worm populations. Microarray studies were performed to identify their genome-wide targets, which were then subjected to further lifespan and genetic analysis to investigate their role in C. elegans aging.

The results indicate that the target pools of both lin-11 and let-711 are enriched for aging genes, since a significant number of tested genes increased lifespan. This enrichment of aging genes in their target pools provides strong evidence that lin-11 and let-711 are indeed regulating the expression of aging genes in adult C. elegans. The data suggests that increased lin-11 expression as well as reduced let-711 expression may be promoting longevity by downregulating the insulin/IGF-1 pathway. Decreasing let-711 may also be contributing to longevity by downregulating the germline signaling pathway.

K11E4.2, R53.5, C49A9.2 and Y82E9BR.5 are four genes from the lin-11 target pool, whose knockdown produced increases inlifespan. These are unannotated genes, and the details of their roles in aging regulation are not known at this point. ins-3 expression was downregulated two-fold upon knockdown of lin-11, suggesting the possible involvement of lin-11 in regulation of the insulin/IGF-1 pathway. An RNAi construct for ins-3 was not available and it is not known whether loss of ins-3 leads to lifespan extension.

let-711 knockdown resulted in an almost four-fold reduction in pdk-1 expression. pdk-1 is an integral part of the insulin/IGF-1 pathway and its knockdown by RNAi extended lifespan. Four other genes from the let-711 target pool that increased lifespan, cdc-25.1, gna-2, meg-1 and ooc-3, all have germline specific functions. The extensions in lifespan generated by these genes were completely dependent on DAF-16. Furthermore, for gna-2, meg-1 or ooc-3, they were independent of DAF-2. These results agree with previously established mechanisms for germline regulation of aging, suggesting the involvement of let-711 in regulating the germline-signaling pathway.

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Biology Commons

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