title: Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7.
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 dose-dependently 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.
authors: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors: Thuy T
authors: TT
authors: Nguyen
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
authors: Samuel W
authors: SW
authors: Caito
authors: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors: William E
authors: WE
authors: Zackert
authors: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: James D
authors: JD
authors: West
authors: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Shijun
authors: S
authors: Zhu
authors: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Michael
authors: M
authors: Aschner
authors: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors: Joshua P
authors: JP
authors: Fessel
authors: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: L Jackson
authors: LJ
authors: Roberts
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D050783:Proto-Oncogene Proteins c-ets; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins
keywords: C. elegans; ETS transcription factors; SIR-2.1; aging; oxidative stress