Copper dysregulation is directly linked to ageing, with increased labile hepatic copper activity contributing to oxidative stress and reduced protective enzyme function. Ageing is associated with an imbalance in metal homeostasis, particularly involving copper, a redox-active metal that generates reactive oxygen species. This oxidative stress contributes to age-related diseases such as neurodegeneration, cancer, and organ failure. However, the role of copper activity in ageing remains poorly understood. Understanding these mechanisms could provide valuable therapeutic targets to mitigate the detrimental effects of ageing and improve overall health outcomes.
This study developed activity-based imaging probes to detect Cu(I) levels with high sensitivity and examined copper activity in ageing liver tissue. Researchers observed a significant increase in labile hepatic copper activity in aged mice, which corresponded with a decline in ALDH1A1, a key hepatic enzyme that protects against oxidative damage. Additionally, a marked decrease in hepatic glutathione activity was detected using non-invasive photoacoustic imaging. To assess whether copper chelation could restore balance, aged mice were treated with ATN-224, a copper chelator, in a longitudinal study. This treatment effectively improved copper homeostasis and preserved ALDH1A1 activity, suggesting a potential strategy for reducing oxidative damage in ageing tissues.
These findings highlight copper dysregulation as a significant factor in ageing and offer a promising therapeutic approach through copper chelation. The study provides critical insights into the impact of metal ion imbalances on ageing-related diseases and suggests that targeting copper activity may help slow or mitigate these effects. From a clinical perspective, interventions that restore copper balance could be explored for age-related conditions such as neurodegeneration and organ decline. Jenna Lorge, EMJ
Reference
Zhao Z et al. Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion. Nat Commun. 2025;DOI:10.1038/s41467-025-56585-4.
