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

Zhenxiang Zhao, Melissa Y Lucero, Shengzhang Su, Eric J Chaney, Jiajie Jessica Xu, Michael Myszka, Jefferson Chan

Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that elevated labile copper promotes liver aging through the depletion of ALDH1A1 activity. This research is relevant as it investigates a potential root cause of aging related to copper dysregulation and offers a therapeutic strategy to mitigate its effects, contributing to the understanding of aging mechanisms.

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