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. SummaryProtein homeostasis is constantly challenged by reactive metabolic intermediates that drive aberrant post-translational modifications, contributing to aging and metabolic disease. While the antioxidant systems that neutralize reactive oxygen species (ROS) are well characterized, whether analogous defenses exist against reactive acyl species (RAS)--the metabolic drivers of non-enzymatic protein acylation, termed carbon stress--has remained unknown. Here we show that three abundant endogenous nucleophilic metabolites--taurine, spermidine, and ethanolamine--directly intercept reactive acyl-CoA species through nucleophilic attack, preventing aberrant protein acylation. We demonstrate that spermidine scavenges acetyl-CoA within the catalytic pocket of the histone acetyltransferase p300, effectively buffering p300-mediated hyperacetylation of muscle, cytosolic, and mitochondrial proteins and extending lifespan in a Drosophila model of p300-driven toxicity. In mice fed a high-fat diet, taurine supplementation promotes the formation of N-fatty acyl taurines, providing direct in vivo evidence for nucleophilic scavenging of diet-derived RAS. Our findings reveal a previously unrecognized metabolite-based defense system--parallel to classical antioxidant defenses against ROS--that neutralizes carbon stress, with broad implications for understanding the molecular mechanisms of aging and the long-observed but mechanistically unexplained health benefits of taurine and spermidine.