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Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion
Zhenxiang Zhao1,2, Melissa Y Lucero1,2, Shengzhang Su1,2
1Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Nature Communications
|February 20, 2025
Summary
Aging increases copper activity in the liver, decreasing protective enzymes. Copper chelation therapy may restore balance and combat aging effects, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Gerontology
- Medical Imaging
Background:
- Oxidative stress is a key factor in aging and associated diseases.
- Copper (Cu) dysregulation contributes to the aging process by generating reactive oxygen species (ROS).
Purpose of the Study:
- To develop activity-based imaging probes for sensitive detection of Cu(I).
- To investigate the relationship between copper activity, aging, and protective hepatic enzymes.
Main Methods:
- Development of novel activity-based imaging probes for Cu(I).
- Noninvasive photoacoustic imaging to assess hepatic glutathione (GSH) activity.
- Longitudinal studies in aged mice treated with a copper chelator (ATN-224).
Main Results:
- Labile hepatic Cu(I) activity increases with age, correlating with decreased ALDH1A1 activity.
- Age-related decline in hepatic GSH activity was observed.
- ATN-224 treatment improved copper homeostasis and preserved ALDH1A1 activity in aged mice.
Conclusions:
- Copper dysregulation is directly linked to the aging process.
- The developed probes offer sensitive detection of Cu(I) activity.
- Copper chelation presents a potential therapeutic strategy for mitigating aging effects.

