Pro-oxidant shift in glutathione redox state during aging.
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.
Rebrin
Igor
I
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA.
Sohal
Rajindar S
RS
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002149:Energy Intake; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis* / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*
D000975:Antioxidants; D006710:Homocysteine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide