New directions for studying the role of free radicals in aging.

Oxidative damage caused by free radicals in vivo is believed to play an important role in the etiology of aging and age-associated degenerative diseases. The most direct evidence supporting this theory is the recent finding that the transgenic Drosophila that overexpress the antioxidant enzymes catalase and superoxide dismutase exhibit an increase in life span. Although the increase in life span in Drosophila by these enzymes is certainly important, the next logical direction is to demonstrate whether increased antioxidant protection occurs similarly in mammals. Several transgenic mouse models that overexpress antioxidant enzymes are currently available. However, one major shortcoming in using these transgenic mice is the difficulty of producing antioxidant overexpression in more than a few tissues. Despite the potential shortcomings of using transgenic mice, these animals provide a unique system in which individual components of a complex system, such as the antioxidant defense system, can be modulated and examined independently. Transgenic mice are therefore potentially powerful tools to study the role of various components of the antioxidant system in the aging process. A parallel direction in the study of free radical roles in aging is to investigate the modulation of transcription factors by oxidative stress. Among these, the transcription factors, NF-κB and AP-1 are implicated in oxidative stress. The activities of these oxidative stress-response transcription factors are regulated by upstream signaling molecules, which involve a cascade of phosphorylation and dephosphorylation events leading to their activation. In this article, we review recent studies that use molecular approaches to investigate the biological role of oxidant stress. Each of these studies potentially provide new insights into the roles of free radicals and free radical damage in the aging process.