Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7

Thuy T. Nguyen, Samuel W. Caito, William E. Zackert, James D. West, Shijun Zhu, Michael Aschner, Joshua P. Fessel, L. Jackson Roberts

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Isoketals (IsoKs) are highly reactive γ-ketoaldehyde products of lipid peroxidation that covalently adduct lysine side chains in proteins, impairing their function. Using C. elegans as a model organism, we sought to test the hypothesis that IsoKs contribute to molecular aging through adduction and inactivation of specific protein targets, and that this process can be abrogated using salicylamine (SA), a selective IsoK scavenger. Treatment with SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age-related biochemical and functional changes. Testing of a variety of molecular targets for SA's action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA-dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SA's longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dosedependently increases ets-7 mRNA levels in non-functional SIR-2.1 mutant, suggesting that both are necessary for SA's complete lifespan and healthspan extension.

Original languageEnglish (US)
Pages (from-to)1759-1780
Number of pages22
JournalAging
Volume8
Issue number8
DOIs
StatePublished - 2016

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Caenorhabditis elegans
T Cell Transcription Factor 1
Lipid Peroxidation
Lysine
Proteins
Gene Expression
Messenger RNA
Genes

Keywords

  • Aging
  • C. elegans
  • ETS transcription factors
  • Oxidative stress
  • SIR-2.1

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. / Nguyen, Thuy T.; Caito, Samuel W.; Zackert, William E.; West, James D.; Zhu, Shijun; Aschner, Michael; Fessel, Joshua P.; Roberts, L. Jackson.

In: Aging, Vol. 8, No. 8, 2016, p. 1759-1780.

Research output: Contribution to journalArticle

Nguyen, Thuy T. ; Caito, Samuel W. ; Zackert, William E. ; West, James D. ; Zhu, Shijun ; Aschner, Michael ; Fessel, Joshua P. ; Roberts, L. Jackson. / Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. In: Aging. 2016 ; Vol. 8, No. 8. pp. 1759-1780.
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