title: The free radical theory of aging revisited: the cell signaling disruption theory of aging.
abstract: CONCLUSIONS
  The free radical theory of aging has provided a theoretical framework for an enormous amount of work leading to significant advances in our understanding of aging. Up to the turn of the century, the theory received abundant support from observations coming from fields as far apart as comparative physiology or molecular biology.
  
  
  BACKGROUND
  Work from many laboratories supports the theory, for instance showing that overexpression of antioxidant enzymes results in increases in life-span. But other labs have shown that in some cases, there is an increased oxidative stress and increased longevity. The discovery that free radicals can not only cause molecular damage to cells, but also serve as signals; led to the proposal that they act as modulators of physiological processes. For instance, reactive oxygen species (ROS) stimulate physiological adaptations to physical exercise.
  
  
  RESULTS
  A critical blow to the free radical theory of aging came from epidemiological studies showing that antioxidant supplementation did not lower the incidence of many age-associated diseases but, in some cases, increased the risk of death. Moreover, recent molecular evidence has shown that increasing generation of ROS, in some cases, increases longevity.
  
  
  CONCLUSIONS
  Gerontologists interested in free radical biology are at a crossroads and clearly new insights are required to clarify the role of ROS in the process of aging. The hurdles are, no doubt, very high, but the intellectual and practical promise of these studies is of such magnitude that we feel that all efforts will be generously rewarding.
authors.affiliation: Department of Physiology, University of Valencia and Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Valencia 46010, Spain. jose.vina@uv.es
authors.forename: Jose
authors.initials: J
authors.lastname: Viña
authors.forename: Consuelo
authors.initials: C
authors.lastname: Borras
authors.forename: Kheira M
authors.initials: KM
authors.lastname: Abdelaziz
authors.forename: Rebeca
authors.initials: R
authors.lastname: Garcia-Valles
authors.forename: Mari Carmen
authors.initials: MC
authors.lastname: Gomez-Cabrera
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D008930:Mitochondria, Liver / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D005609:Free Radicals