Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic stem cell depletion

08 September 2023, Version 1

Abstract

Oxidative stress is one of the major culprits of aging and age-related disease states. Although the body features numerous antioxidant defense systems to safeguard against this, conditions ranging from neurodegeneration and cancer to organ failure may result once the buffering capacity of these protective mechanisms have been exceeded. While it is known that redox active metal ions such as copper (Cu) can generate reactive oxygen species (ROS), establishing a possible connection between Cu dysregulation and aging, especially in an in vivo context is exceedingly difficult. Through the development of new activity-based imaging probes for Cu(I) exhibiting ultra-sensitivity, we discovered that labile hepatic Cu activity increases during aging, and this results in the depletion of hepatic stem cells (hSCs) as measured by the ALDH1A1 stemness biomarker. Further, the application of a glutathione (GSH)-responsive probe for noninvasive photoacoustic imaging revealed that these findings are linked to an age-dependent decrease of hepatic GSH activity. To delay this phenotype, we designed two longitudinal studies where aged-mice were treated with ATN-224, a Cu-chelating drug. Our results suggest that treatment restores Cu homeostasis which may have a hSC-sparing effect to delay the onset of liver aging.

Content

Supplementary materials

Supporting Information
Supporting Information

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.