Zhao Zhenxiang, Lucero Melissa Y, Su Shengzhang, Chaney Eric J, Xu Jiajie Jessica, Myszka Michael, Chan Jefferson
Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Beckman Institute for Advanced Science and Technology, and Cancer Center of Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Nat Commun. 2025 Feb 20;16(1):1794. doi: 10.1038/s41467-025-56585-4.
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.
氧化应激在衰老及相关疾病（包括神经退行性变、癌症和器官衰竭）中起关键作用。铜（Cu）作为一种具有氧化还原活性的金属离子，可产生活性氧（ROS），其失调会导致衰老。在此，我们开发了基于活性的成像探针用于灵敏检测Cu(I)，并表明不稳定的肝脏Cu活性随年龄增长而增加，这与保护性肝脏酶ALDH1A1活性的下降平行。我们还通过无创光声成像观察到肝脏谷胱甘肽（GSH）活性随年龄增长而降低。使用这些探针，我们对接受铜螯合剂ATN-224治疗的老年小鼠进行了纵向研究，并证明这种治疗可改善铜稳态并保留ALDH1A1活性。我们的研究结果揭示了铜失调与衰老之间的直接联系，深入了解了其作用，并提供了一种减轻其影响的治疗策略。
