Endogenous nucleophilic scavengers of reactive acyl-species neutralize carbon stress

Abstract

Aberrant protein acylation by reactive acyl species (RAS), termed carbon stress, is a major driver of aging and metabolic disease. While enzymatic deacylases such as sirtuins counteract aberrant acylation, whether endogenous metabolites can directly neutralize RAS remains unclear. Here, we report that nucleophilic metabolites (taurine, spermidine, and ethanolamine) react with acyl-CoAs, preventing aberrant protein acylation and potentially extending lifespan. We demonstrate that spermidine scavenges acetyl-CoA within the catalytic pocket of p300, a histone acetyltransferase, and extends lifespan in Drosophila. Taurine supplementation in mice fed a high-fat diet promotes N-fatty acyl taurine formation, confirming in vivo scavenging of RAS. These findings identify endogenous nucleophilic metabolites as scavengers that neutralize carbon stress, with implications for combating aging and metabolic disease.