The mitochondrial free radical theory of ageing--where do we stand?

Understanding the molecular mechanisms underlying the ageing process may provide the best strategy for addressing the challenges posed by ageing populations worldwide. One theory proposing such molecular mechanisms was formulated 50 years ago. Harman et al. suggested that ageing might be mediated by macromolecular damage through reactions involving reactive oxygen species (ROS). Today, a version of the free radical theory of ageing, focusing on mitochondria as source as well as target of ROS, is one of the most popular theories of ageing. Here we critically review the status of key principles and concepts on which this theory is based. We find that the evidence to date shows that many of the original assumptions are questionable, while on some critical issues further refinements in techniques are required. Even so, it is becoming evident that mitochondria and mtDNA integrity may indeed be crucial determinants of organismal ageing. Implications for the prospect of successful interventions as well as evidence for and against efficacy of current therapeutic approaches are discussed.