Oxidative stress in C. elegans: Discovery of a mechanistic role for gamma-ketoaldehyde lipid peroxidation products in the Free Radical Theory of Aging

Abstract

Highly reactive acyclic levuglandin-like gamma-ketoaldehydes (gamma-KA, isoketals, or IsoKs) are formed as products of the isoprostane pathway of lipid peroxidation. IsoKs are known to covalently adduct ε-amino groups in lysyl residues of proteins, forming stable adducts and intramolecular cross-links. Increased IsoK-lysyl-lactam adducts are found in a number of disease conditions, including atherosclerosis, end-stage renal disease, and Alzheimer’s disease. A selective IsoK scavenger, salicylamine (SA), was developed and tested in Caenorhabditis elegans to probe the pathophysiological processes in IsoK-mediated oxidative injury, and consequently provide the groundwork for the development of new rational therapeutic interventions to limit oxidative damage. Administration of 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.