Research Paper Volume 8, Issue 8 pp 1759—1780
Scavengers of reactive γ-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7
- 1 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
- 2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- 3 Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
- 4 Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
- 5 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- 6 Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Received: May 9, 2016 Accepted: July 20, 2016 Published: August 9, 2016
https://doi.org/10.18632/aging.101011How to Cite
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.