Free radicals: key to brain aging and heme oxygenase as a cellular response to oxidative stress

J Gerontol A Biol Sci Med Sci. 2004 May;59(5):478-93. doi: 10.1093/gerona/59.5.m478.


Aging is one of the unique features in all organisms. The impaired functional capacity of many systems characterizes aging. When such impairments occur in the brain, the susceptibility to neurodegenerative diseases amplifies considerably. The free radical theory of aging posits that the functional impairments in brains are due to the attack on critical cellular components by free radicals, reactive oxygen species, and reactive nitrogen species produced during normal metabolism. In this review, we examine this concept based on the parameters of oxidative stress in correlation to aging. The parameters for lipid peroxidation are phospholipid composition, reactive aldehydes, and isoprostanes. The parameters for protein oxidation are protein carbonyl levels, protein 3-nitrotyrosine levels, electron paramagnetic resonance, and oxidative stress-sensitive enzyme activities. We conclude that free radicals are, at least partially, responsible for the functional impairment in aged brains. The aging brain, under oxidative stress, responds by induction of various protective genes, among which is heme oxygenase. The products of the reaction catalyzed by heme oxygenase, carbon monoxide, iron, and biliverdin (later to bilirubin) each have profound effects on neurons. Although there may be other factors contributing to brain aging, free radicals are involved in the damaging processes associated with brain aging, and cellular stress response genes are induced under free radical oxidative stress. Therefore, this review supports the proposition that free radicals are, indeed, a key to brain aging.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Aging / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / physiology
  • Cells / metabolism
  • Free Radicals*
  • Heat-Shock Proteins / physiology
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / physiology*
  • Humans
  • Lipid Peroxidation
  • Oxidation-Reduction
  • Oxidative Stress*
  • Proteins / metabolism


  • Free Radicals
  • Heat-Shock Proteins
  • Proteins
  • Heme Oxygenase (Decyclizing)