Significance: Oxidative stress in moderation positively affects homeostasis through signaling, while in excess it is associated with adverse health outcomes. Both activities are generally attributed to reactive oxygen species (ROS); hydrogen peroxide as the signal, and cysteines on regulatory proteins as the target. However, using antioxidants to affect signaling or benefit health has not consistently translated into expected outcomes, or when it does, the mechanism is often unclear. Recent Advances: Reactive sulfur species (RSS) were integral in the origin of life and throughout much of evolution. Sophisticated metabolic pathways that evolved to regulate RSS were easily "tweaked" to deal with ROS due to the remarkable similarities between the two. However, unlike ROS, RSS are stored, recycled, and chemically more versatile. Despite these observations, the relevance and regulatory functions of RSS in extant organisms are generally underappreciated. Critical Issues: A number of factors bias observations in favor of ROS over RSS. Research conducted in room air is hyperoxic to cells, and promotes ROS production and RSS oxidation. Metabolic rates of rodent models greatly exceed those of humans; does this favor ROS? Analytical methods designed to detect ROS also respond to RSS. Do these disguise the contributions of RSS? Future Directions: Resolving the ROS/RSS issue is vital to understand biology in general and human health in particular. Improvements in experimental design and analytical methods are crucial. Perhaps the most important is an appreciation of all the attributes of RSS and keeping an open mind.
Keywords: ROS; RSS; evolution; oxidative stress; signaling; sulfur metabolism.