NEW DIRECTIONS FOR STUDYING THE ROLE OF FREE-RADICALS IN AGING

Oxidative damage caused by free radicals in vivo is believed to play a n important role in the etiology of aging and age-associated degenerat ive diseases. The most direct evidence supporting this theory is the r ecent finding that the transgenic Drosophila that overexpress the anti oxidant enzymes catalase and superoxide dismutase exhibit an increase in life span, Although the increase in life span in Drosophila by thes e enzymes is certainly important, the next logical direction is to dem onstrate whether increased antioxidant protection occurs similarly in mammals, Several transgenic mouse models that overexpress antioxidant enzymes are currently available. However, one major shortcoming in usi ng these transgenic mice is the difficulty of producing antioxidant ov erexpression in more than a few tissues. Despite the potential shortco mings of using transgenic mice, these animals provide a unique system in which individual components of a complex system, such as the antiox idant defense system, can be modulated and examined independently. Tra nsgenic mice are therefore potentially powerful tools to study the rol e 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 st ress, Among these, the transcription factors, NF-kappa B and AP-1 are implicated in oxidative stress. The activities of these oxidative stre ss-response transcription factors are regulated by upstream signaling molecules, which involve a cascade of phosphorylation and dephosphoryl ation events leading to their activation, In this article, we review r ecent studies that use molecular approaches to investigate the biologi cal role of oxidant stress. Each of these studies potentially provide new insights into the roles of free radicals and free radical damage i n the aging process.