Interactions between oxidative stress and insulin/IGF-1 signaling for starvation resistance in Caenorhabditis elegans

Abstract

Reactive oxygen species (ROS) are a natural byproduct of metabolism with roles in cell signaling and homeostasis but also generate oxidative stress. Past research demonstrates that ROS are a major factor in pathological conditions and the aging process in Caenorhabditis elegans and other organisms. Additionally, transcription factor gene daf-16 from the insulin/IGF-1 signaling (IIS) pathway is thought to help manage oxidative stress to mitigate such consequences, which may be partly due to endogenous antioxidant genes downstream of it. Furthermore, exogenous antioxidant drugs such as N-acetylcysteine (NAC) have been found to extend mean and maximum survival time in C. elegans under a variety of conditions, including exposure to oxidative stress, high heat, and UV radiation. However, their effects on starvation resistance have not yet been examined. To uncover how the IIS pathway interacts with ROS and antioxidants in C. elegans, we performed assays for two measures of starvation resistance: starvation survival and growth rate following starvation, which enabled us to investigate how the presence and absence of ROS impacted the starvation recovery process. We demonstrated that NAC can significantly increase and decrease survival in wild-type worms in a dose-dependent manner. Additionally, NAC also increased worm length, a metric of their growth rate. In contrast, daf-16 mutants exposed to NAC had decreased size and survival. Moreover, mutating endogenous antioxidant genes downstream of daf-16 did not cause a significant decrease in worm survival. These complex interactions between IIS and NAC suggest that genotype may position worms at different baselines on a hormesis curve for antioxidants and consequently alter their sensitivity to ROS quenching.