Pro-oxidant shift in glutathione redox state during aging

Adv Drug Deliv Rev. Oct-Nov 2008;60(13-14):1545-52. doi: 10.1016/j.addr.2008.06.001. Epub 2008 Jul 4.


The GSH:GSSG ratio, which is the primary determinant of the cellular redox state, becomes progressively more pro-oxidizing during the aging process due to an elevation in the GSSG content and a decline in the ability for de novo GSH biosynthesis. The K(m) of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH biosynthesis, significantly increases during aging, which would adversely affect the ability for rapid GSH biosynthesis, especially under stressful conditions. Experimental studies suggest that age-related accumulation of homocysteine, an intermediate in the trans-sulfuration pathway, may be responsible for causing the loss of affinity between GCL and its substrates. Over-expression of GCL has been shown to prolong the life span of Drosophila by up to 50%, suggesting that perturbations in glutathione metabolism play a causal role in the aging process.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Aging / metabolism*
  • Animals
  • Antioxidants / metabolism
  • Energy Intake
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / biosynthesis*
  • Glutathione / metabolism
  • Glutathione Disulfide / metabolism
  • Homocysteine / metabolism
  • Humans
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / physiology*


  • Antioxidants
  • Homocysteine
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Glutathione Disulfide