Pro-oxidant shift in glutathione redox state during aging☆
Introduction
An invariable feature of the life cycle of all multi-cellular organisms is that following a period of growth and reproduction there is a gradual decline in physiological fitness, and the ability to maintain homeostasis is progressively whittled, which inevitably culminates in the death of the organism. The nature of the mechanisms causing the various age-associated physiological decrements or those that determine the vast differences in the maximum life spans of various species are presently poorly understood. Among the many candidate causal hypotheses, one that has gained considerable interest postulates that senescent physiological changes emanate from the deleterious effects of reactive oxygen species (ROS), generated during cellular metabolism. This hypothesis, often referred to as the “oxidative stress hypothesis”, was originally advanced in 1956 [1], an era when there was relatively little understanding of the mechanisms of ROS production or the nature of their interactions with biomacromolecules. Nevertheless, considerable progress has since been made in understanding the role of ROS in the aging process, primarily due to the contemporaneous advances in the biochemistry of ROS. The main focus of current investigations is the elucidation of the mechanism by which ROS cause attenuations in specific cellular functions, which govern the progression of senescence and determine the species-specific maximum life spans.
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Oxidative stress, redox state and the aging process
Historically, ROS were generally regarded as potentially toxic and physiologically costly products of aerobic metabolism [2], [3]. Their formation was assigned to some intrinsic biochemical and/or structural flaws(s), requiring considerable expenditure of metabolic resources for their detoxification. In this view, ROS served no useful function, and if not totally eliminated by the anti-oxidant defenses, they would inflict random macromolecular damage, whose accumulation with age would cause
Glutathione homeostasis
The intra-cellular concentration of GSH (γ-l-glutamylcysteinylglycine), a tripeptide, often approaches millimolar amounts in mammals; however, GSH concentration varies in different cellular compartments, implying that distinct intra-cellular redox microenvironments exist within different organelles. For instance, GSH levels are much lower in the nucleus than in the cytoplasm, but the nuclear GSH content increases during cell division [13]. There is increasing realization that intra-cellular
Analytical procedures for measurement of glutathione and estimation of the redox potential
Measurements of GSH and GSSG in biological specimens can be erroneously affected during procedural handling due to the artificial oxidation of GSH. Analytical procedures in earlier studies, employing colorimetric, fluorimetric, and enzymatic assays were eventually found to have low sensitivity, inadequate specificity and/or low reproducibility [10], [12], [30]. Later procedures employing high-performance liquid chromatography, in combination with UV-absorbance or fluorescence detection, were
Effect of age on glutathione redox state in mice
Comparisons of the amounts of GSH, GSSG and protein–glutathione (protein–SSG) disulfides and GSH:GSSG ratios in homogenates and mitochondria of different tissues (liver, kidney, heart, brain, eye, and testis) were made between 4-, 10-, 22- and 26-month-old C57BL/6 mice [26]. In 4-month-old mice, GSH content of tissue homogenates varied ~ 10-fold among different tissues, with the rank order: liver = testis > brain = heart > eye > kidney. GSSG content of tissue homogenates also varied ~ 10-fold. The GSH:
Mechanisms of age-related oxidizing shift in glutathione redox state
The two main factors affecting the glutathione redox state during the aging process in the mouse seemed to be an increase in GSSG concentration and a decrease in the GSH pool size. In virtually all tissues, GSSG concentration is elevated during the last trimester of life. This is accompanied by an increase in the rates of mitochondrial superoxide and hydrogen peroxide production [34], [35], [36]. These two ROS are progenitors of a variety of other, some highly reactive, ROS. Age-related
Effects of caloric restriction on glutathione redox state in mouse
A decrease in the amount of food consumption, relative to the ad libitum (AL) fed level, has been shown to extend life span of certain laboratory strains of mice and rats [39], [40]. There is also some evidence that caloric restriction (CR) retards the onset and progression of some age-associated changes linked to oxidative stress. A comparison between 22-month-old AL mice and those fed a diet containing 40% fewer calories than the AL group since the age of 4 months, indicated that CR had no
Effects of dietary anti-oxidants on glutathione
The question whether intake of low molecular weight anti-oxidants causes a lowering of the level of oxidative stress has been intensely debated in the literature [36], [41], [42]. We addressed this issue by determining the effect of long term (8–10 months) dietary supplementation with two different mixtures of anti-oxidants on the glutathione redox state in senescence-accelerated mice (SAM-P8) [29]. Diet I was enriched with vitamin E, vitamin C, l-carnitine, and lipoic acid, while Diet II
Glutathione redox state in aging Drosophila melanogaster
The fruit fly (Drosophila melanogaster) provides several relative advantages as an experimental model for investigating the relationship between oxidative stress and aging, such as: i) relatively short life span (~ 8 weeks), ii) ability to manipulate the metabolic rate and life expectancy of flies by varying the ambient temperature, iii) availability of mutants and transformants (over-expressors). Glutathione redox state, amounts of the redox sensitive aminothiols (cysteine, Cys–Gly and
Role of glutathione in disease and toxicity
Depletion of glutathione or a disturbance in its redox state can lead not only to the disruption of a variety of cellular activities, but also to sensitization of cells to toxicants, thereby causing drug-induced cell toxicity. Indeed, some drugs have been shown to affect glutathione redox couple and mitochondrial function; e.g., usnic acid, a key constituent of LipoKinetix (a dietary supplement marketed as a weight-loss agent), can induce hepatic necrosis, triggered by GSH depletion and
Acknowledgements
Our research has been supported by grants RO1 AG 13563 and RO1 AG 7657 from National Institutes of Health—National Institute on Aging.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Mitochondrial Medicine and Mitochondrion-Based Therapeutics”.