Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection

Ehud Cohen, Deguo Du, Derek Joyce, Erik A. Kapernick, Yuli Volovik, Jeffery W. Kelly, Andrew Dillin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Toxic protein aggregation (proteotoxicity) is a unifying feature in the development of late-onset human neurodegenerative disorders. Reduction of insulin/IGF-1 signaling (IIS), a prominent lifespan, developmental and reproductive regulatory pathway, protects worms from proteotoxicity associated with the aggregation of the Alzheimer's disease-linked Aβ peptide. We utilized transgenic nematodes that express human Aβ and found that late life IIS reduction efficiently protects from Aβ toxicity without affecting development, reproduction or lifespan. To alleviate proteotoxic stress in the animal, the IIS requires heat shock factor (HSF)-1 to modulate a protein disaggregase, while DAF-16 regulates a presumptive active aggregase, raising the question of how these opposing activities could be co-regulated. One possibility is that HSF-1 and DAF-16 have distinct temporal requirements for protection from proteotoxicity. Using a conditional RNAi approach, we found an early requirement for HSF-1 that is distinct from the adult functions of DAF-16 for protection from proteotoxicity. Our data also indicate that late life IIS reduction can protect from proteotoxicity when it can no longer promote longevity, strengthening the prospect that IIS reduction might be a promising strategy for the treatment of neurodegenerative disorders caused by proteotoxicity.

Original languageAmerican English
Pages (from-to)126-134
Number of pages9
JournalAging Cell
Volume9
Issue number2
DOIs
StatePublished - Apr 2010

Keywords

  • Caenorhabditis elegans
  • Insulin/IGF-1 signaling
  • Longevity
  • Proteotoxicity

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