Oxidative Stress, Gene Expression, and the Aging Process

Abstract

Oxidative stress plays a causative role in the development of age-related degenerative diseases and may be an underlying determinant of the aging process itself. In this review, we summarize the evidence from a variety of experimental systems that supports this hypothesis. We discuss the molecular basis for the control of gene expression by oxidants, with particular focus on recent studies demonstrating the activation of mitogen-activated protein kinase signal transduction by oxidative stress. How alterations in such pathways may contribute to aging is addressed, and specific examples of transcription factors whose activities are altered both by oxidants and with aging are given. We provide a model illustrating the multiple sites in signal transduction pathways sensitive to oxidative stress, which may indicate targets for strategies aiming to retard or reverse age-related phenotypic changes.

OXIDATIVE STRESS IN AGING: CURRENT VIEWS AND HYPOTHESES
Exposure to reactive oxygen intermediates (ROI), including molecular oxygen, superoxide, hydrogen peroxide (H₂O₂), and hydroxyl radicals, occurs ubiquitously in an aerobic environment. Accordingly, aerobic organisms have widely adapted oxidation-reduction reactions to function in key metabolic and regulatory pathways necessary for normal cell growth. In addition, a number of defense mechanisms to control the level of ROI have evolved as an accessory to these processes. However, when ROI and other oxidizing species exceed the cellular antioxidant capacity, oxidative stress results and oxidative damage to lipids, protein, and DNA ensues. The accumulation of oxidative modifications as a causative factor in aging and degenerative processes was originally proposed by Harman 40 years ago (Harman...