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

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.