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Translational control mediates lifespan extension due to dietary restriction in Drosophila

Citation

Zid, Brian M (2008) Translational control mediates lifespan extension due to dietary restriction in Drosophila. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-02052008-020618

Abstract

Aging is characterized by the declining ability of an organism to maintain homeostasis, which eventually leads to death. Dietary restriction (DR), the reduction of nutrients without malnutrition, extends lifespan in various organisms, yet its molecular underpinnings are poorly understood. We show that in Drosophila, DR upregulates the translational repressor 4EBP, the eukaryotic translation initiation factor 4E binding protein, and that this upregulation is necessary for the full lifespan extension upon DR and sufficient to extend lifespan on a nutrient rich diet. Investigation of the genome-wide translational changes upon DR using translation state array analysis (TSAA) found that translationally downregulated genes tend to have extensive 5’ untranslated regions (UTR) secondary structures, while those that are upregulated have weakly structured 5’UTRs. Among the translationally upregulated genes, mitochondrial ribosomal proteins and electron transport chain components were overrepresented. Mitochondrial genes were found to have weakly structured 5’UTRs in Drosophila, and this was conserved in Humans. The 5’UTRs of mitochondrial genes were found to be sufficient to confer preferential translation during times of high 4EBP activity in a cap-independent manner to reporter constructs. Upregulation of mitochondrial function was verified and found to be d4EBP dependent, implicating a novel mechanism for regulating mitochondrial function upon DR. These results implicate mRNA translation initiation in modulating lifespan and mitochondrial function upon DR.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:aging; dietary restriction; translation
Degree Grantor:California Institute of Technology
Division:Biology
Major Option:Biology
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Benzer, Seymour
Thesis Committee:
  • Campbell, Judith L. (co-chair)
  • Benzer, Seymour (co-chair)
  • Varshavsky, Alexander J.
  • Sternberg, Paul W.
  • Deshaies, Raymond Joseph
Defense Date:17 January 2008
Author Email:zid (AT) caltech.edu
Record Number:CaltechETD:etd-02052008-020618
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-02052008-020618
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:504
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:21 Feb 2008
Last Modified:26 Dec 2012 02:30

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