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

Pro-oxidant shift in glutathione redox state during aging.

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Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA.


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.

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