Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion.

Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.