Box 1. Oxidants and diseases of ageing

Although maximum life span is the most relevant and defined endpoint with regard to ageing, it seems likely that in large multicellular organisms ageing need not proceed uniformly. This concept of non-uniform or focal ageing, or what has been termed segmental progeria by others⁸³, may be particularly important in a variety of age-related human diseases. Certainly the incidence of a host of diseases, including both cardiovascular and neurodegenerative disorders, increases exponentially with age. The basis for this steep rise in disease incidence is unexplained, but one possibility is that such diseases may share common mechanisms with ageing. In this regard, increasing evidence indicates that reactive oxygen species (ROS) may participate in the pathogenesis of these diseases. In support of this notion is the experimental evidence that the vessel wall of patients with atherosclerotic risk factors, but no overt disease, is characterized by a significant increase in vascular ROS production⁸⁶. In addition, many ophthalmological and neurodegenerative diseases seem to be mediated, at least in part, by oxidative stress.

One common feature to many of these conditions is the recruitment of inflammatory cells. These cells contribute to oxidative stress in large part because they contain the potent NADPH oxidase system. Once activated, the NADPH oxidase complex, which is present in neutrophils, macrophages, microglia and vascular cells, produces large amounts of superoxide. In both the brain and the vessel wall the interaction of superoxide with endogenously generated nitric oxide can lead to the formation of peroxynitrite and other damaging radical species. Although the relative contribution of these various radical species is unknown, the link between inflammation and ROS seems to provide a useful framework for understanding disease progression.

Although laboratory data clearly suggest a role for oxidants in the pathogenesis of many age-related diseases, the clinical use of antioxidant therapy has been at best equivocal. Indeed, most of the large randomized trials of antioxidant vitamins such as vitamin A and vitamin E have shown, at best, marginal results and occasionally, potentially harmful outcomes (see below). Nonetheless, antioxidant therapy is in its infancy and issues of dosing and duration remain largely unexplored. It therefore is interesting to speculate that, in contrast to the relatively rare progerias that are characterized by accelerated global ageing, the clinical manifestations of these more common diseases, namely an atherosclerotic plaque or an Alzheimer tangle, may represent the fingerprint of accelerated but focal ageing.