Prospects & Overviews Oxidative stress as a cost of reproduction: Beyond the simplistic trade-off model John R. Speakman 1)2)Ã and Michael Garratt 3) The idea that oxidative stress may underpin life history trade- offs has become extremely popular. However, experimental support for the concept has proved equivocal. It has recently been suggested that this might be because of flaws in the design of existing studies. Here, we explore the background to the oxidative stress hypothesis and highlight some of the complexities in testing it. We conclude that the approach recently suggested to be least useful in this context (comparing reproducing to non-reproducing animals) may in fact be the most powerful. Moreover, suggested alternative approaches of limiting food supply or manipulating litter sizes have many complexities and problems. We suggest some useful alternative approaches that have not been previously advocated, particularly the study of individuals reproducing at greater parity later in life. Finally, the measures of oxidative stress and tissues that are analysed influence the experimental outcome. This suggests our conceptual model of the trade-off is currently too simplistic, and that studies based on single or limited numbers of assays, or restricted to single tissues, whether they support or refute the theory, should be interpreted with great caution. Keywords: .life history; oxidative stress Introduction: Oxidative stress as a theoretical cost of reproduction The concept that there are trade-offs in life history parameters is a fundamental aspect of evolutionary ecology [1, 2], and it is widely assumed that there are physiological processes underly- ing such trade-offs [3, 4]. During the last decade interest in these fundamental physiological mechanisms has intensified. One particular idea, that has captured the imagination of the ecological community, is that the trade-off between reproduc- tive investment and survival may be due to free-radical production and oxidative stress. This idea has its origins over 100 years ago, when Rubner [5] observed that the product of lifespan and metabolic rate across species is almost constant. This observation implied that having a high metabolic rate involves either more rapid depletion of some vital compound, or generation of a toxic by-product that is injurious to health. This notion was subsequently encapsulated in the ‘rate of living’ (ROL) theory [6], the idea that living fast is inevitably linked to dying young. The ‘ROL’ theory was given a molecular mechanism in the 1950s when it was noted that during oxidative phosphorylation, the process by which ATP is generated in cells, there is a leak of electrons from the electron transport chain, and that these electrons become involved in promiscuous reactions with free-oxygen, leading to oxygen free-radical production [7, 8]. Such free-radicals are involved in further reactions to form radical oxygen species (ROS) such as the hydroxyl radical (HO • ) that can be extremely toxic, causing oxidative damage to molecules such as lipids, proteins and DNA. Animals have sophisticated systems to neutralise ROS, and additional mechanisms to repair or mitigate the damage. Nevertheless, some damage always evades these systems and consequently oxidative damage accumulates ultimately leading to dysfunction (ageing) and mortality [9]. The disposable soma theory The disposable soma theory [10] was formulated in the 1970s around the concept that individuals have limited resources DOI 10.1002/bies.201300108 1) Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China 2) Institute of Biological and Environmental sciences, University of Aberdeen, Aberdeen, Scotland, UK 3) Evolution and Ecology Research Group and School of Biological, Earth and Environmental Sciences, The University of New South Wales, Sydney, NSW, Australia *Corresponding author: John R. Speakman E-mail: j.speakman@abdn.ac.uk www.bioessays-journal.com 1 Bioessays 35: 0000–0000, ß 2013 WILEY Periodicals, Inc. Problems & Paradigms