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PMID: 18006689 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants.

Genes & development ·Vol. 21 ·No. 22 ·2007-11-15 ·Pages 2976-94

Samuelson AV, Carr CE, Ruvkun G

Abstract

Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the DAF-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. We conducted a genome-wide RNAi screen to identify genes necessary for the extended life span of daf-2 mutants and identified approximately 200 gene inactivations that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the DAF-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and DAF-16. The activities of these genes may normally decline during aging.

MeSH Terms
Animals Caenorhabditis elegans/physiology Caenorhabditis elegans Proteins/genetics Forkhead Transcription Factors Gene Silencing Genes, Helminth Genes, Reporter Green Fluorescent Proteins/metabolism Insulin-Like Growth Factor I/genetics Mutation RNA Interference Receptor, Insulin/genetics Signal Transduction/physiology Superoxide Dismutase/genetics Transcription Factors/genetics
Chemicals
Caenorhabditis elegans Proteins Forkhead Transcription Factors Transcription Factors daf-16 protein, C elegans Green Fluorescent Proteins Insulin-Like Growth Factor I Sod-3 protein, C elegans Superoxide Dismutase DAF-2 protein, C elegans Receptor, Insulin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Samuelson Andrew V
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Carr Christopher E
Ruvkun Gary
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1588907
Published
2007-11-15
Pages
2976-94
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2049198
Subset
IM
Grants
NIA NIH HHS · 5 R01 AG16636 · United States
External Links
PubMed source DOI: 10.1101/gad.1588907 PMC Full Text View journal details
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