Repository logo

Effect of treatment with a Nrf2 activator on in vivo proteostasis in mice




Valenti, Zackary J., author
Hamilton, Karyn L., advisor
Lark, Daniel S., committee member
Gentile, Christoper L., committee member

Journal Title

Journal ISSN

Volume Title


Aging is characterized by progressive declines in cellular function, often resulting from oxidative stress. Redox homeostasis is perturbed when the production of reactive oxygen species (ROS) exceeds the capacity of antioxidant defenses to eliminate ROS. Chronic imbalances in ROS production and clearance can lead to disruptions in proteostasis by causing unrepairable damage to proteins. Nuclear factor erythroid-derived 2-like 2 (Nrf2) exerts transcriptional regulation over endogenous antioxidant defenses by regulating the transcription of antioxidant enzymes and a myriad of cytoprotective proteins. Nrf2 activation has received attention as a therapeutic intervention to preserve cellular function. Our lab has characterized the treatment effects of Protandim and PB125, phytochemical compounds known to activate Nrf2. The collective findings from our group using both in vitro and in vivo experiments suggest that both compounds are effective for improving proteostasis; however, compared to Protandim, PB125 is more efficacious for sustained Nrf2 activation due to its ability to inhibit mechanisms of the Nrf2 shutdown pathway. We speculate that PB125 may have additional benefits on mechanism of proteostasis in vivo; thus, the purpose of the present study was to examine the effects of two doses of PB125 supplementation on proteostasis. We randomly assigned 51 male C57BL6/J mice aged 15-16 months to diets with 0 ppm (CON), 100 ppm (LOW), or 300 ppm (HIGH) doses of PB125 n=18/group during a 5-week feeding study. Mice were isotopically labeled with 8% deuterium oxide (D2O) administered in the drinking water to simultaneously measure protein and DNA synthesis rates in mitochondrial (mito), cytosolic (cyto), and mixed (mixed) subcellular fractions of heart, liver, and skeletal muscle tissues. We hypothesized that mice treated with PB125 would have enhanced proteostasis outcomes; however, our results indicate that PB125 supplementation did not affect mechanisms of proteostasis. No significant differences were found in protein or DNA synthesis rates between treatment groups, and our secondary measures further support that PB125 did not affect the proteostatic network, as there were no significant differences observed in Nrf2-regulated protein expression or protein aggregation. From our data we were able to confirm that oral administration of PB125 is safe; however, further in vivo investigations are warranted in order to confirm the role of PB125 in modulating mechanisms of proteostasis.


Rights Access



Associated Publications