Sex differences in antioxidant defence and the regulation of redox homeostasis in physiology and pathology

Reactive oxygen species (ROS) is a term that defines a group of unstable compounds derived from exogenous sources or endogenous metabolism. Under physiological conditions, low levels of ROS play a key role in the regulation of signal transduction-or transcription-mediated cellular responses. In contrast, excessive and un-controlled loading of ROS results in a pathological state known as oxidative stress (OS), a leading contributor to aging and a pivotal factor for the onset and progression of many disorders. Evolution has endowed cells with an antioxidant system involved in stabilizing ROS levels to a specific threshold, maintaining ROS-induced signalling function and limiting negative side effects. In mammals, a great deal of evidence indicates that females defence against ROS is more proficient than males, determining a longer lifespan and lower incidence of most chronic diseases. In this review, we will summarize the most recent sex-related differences in the regulation of redox homeostasis. We will highlight the peculiar aspects of the antioxidant defence in sex-biased diseases whose onset or progression is driven by OS, and we will discuss the molecular, genetic, and evolutionary determinants of female proficiency to cope with ROS.