title: The oxidative stress theory of disease: levels of evidence and epistemological aspects.
abstract: The theory that oxidative stress (OS) is at the root of several diseases is extremely popular. However, so far, no antioxidant has been recommended or offered by healthcare systems neither has any been approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging ROS might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and at different times. Aggregating this plurality of systems into a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories (open data), as this will allow big data approaches or meta-analyses, without the drawbacks of publication bias.
  
  
  
  This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
authors.affiliation: Brighton & Sussex Medical School, Brighton, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jaquet
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marcucci
authors.affiliation: Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Harald H H W
authors.initials: HHHW
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004194:Disease; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species