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The concentration of glutathione (GSH), the most abundant intracellular nonprotein thiol and
important antioxidant, declines with age and in some age-related diseases. The underlying
mechanism, however, is not clear. The previous studies from our laboratory showed that the age-
dependent decline in GSH content in Fisher 344 rats was associated with a downregulation of
glutamate cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH synthesis. Our recent
studies further indicated that the activity and mRNA content of glutathione synthase (GS), which
catalyzes the second reaction in de novo GSH synthesis, were also decreased with age in some
tissues. No age-associated change was observed in glutathione reductase or gamma-glutamyl
transpeptidase activities. Also, although GSH content declined with age in both male and female
mice, male mice experienced more dramatic age-associated decline in many tissues/organs than
female mice. Furthermore, we found that GSH content was significantly decreased in the red
blood cells from male Alzheimer disease patients, which was associated with decreases in GCL
and GS activities. Finally, we showed that estrogen increased GSH content, GS and GR
activities, and GCL gene expression in the liver of both male and female mice. Taken together,
our results suggest that (1) GCL plays a critical role in maintaining GSH homeostasis under both
physiological and pathological conditions; (2) decreased GSH content may be involved in AD
pathology in humans; and (3) estrogen increases GSH content in mice by multiple mechanisms.
PMID: 15247041 [PubMed - indexed for MEDLINE]
Aberrant Insulin Receptor Signaling and Amino Acid
Homeostasis as a Major Cause of Oxidative Stress in Aging
The mechanisms leading to the increase in free radical-derived oxidative stress in “normal aging”
remains obscure. Here we present our perspective on studies from different fields that reveal a
previously unnoticed vicious cycle of oxidative stress. The plasma cysteine concentrations during
starvation in the night and early morning hours (the postabsorptive state) decreases with age.
This decrease is associated with a decrease in tissue concentrations of the cysteine derivative
and quantitatively important antioxidant glutathione. The decrease in cysteine reflects changes in
the autophagic protein catabolism that normally ensures free amino acid homeostasis during
starvation. Autophagy is negatively regulated by the insulin receptor signaling cascade that is
enhanced by oxidative stress in the absence of insulin. This synopsis of seemingly unrelated
processes reveals a novel mechanism of progressive oxidative stress in which decreasing
antioxidant concentrations and increasing basal (postabsorptive) insulin receptor signaling activity
compromise not only the autophagic protein
catabolism but also the activity of FOXO transcription factors (i.e., two functions that were found
to have an impact on lifespan in several animal models of aging). In addition, the aging-related
decrease in glutathione levels is likely to facilitate certain “secondary” disease-related
mechanisms of oxidative stress. Studies on cysteine supplementation show therapeutic promise.
Antioxid. Redox Signal. 10, 661–678.
http://www.ebmonline.org/cgi/content/full/226/9/866
In later studies, glutathione (GSH) concentrations in various tissues were determined during the
life span. A noteworthy discovery was a sharp decline in tissue GSH levels in the senescent
C57BL/6J mouse and the yellow fever mosquito, Aedes aegypti (2–4). Another key finding was
that the blood GSH profile in the mature and aging mouse was paralleled in less accessible
organs such as heart, liver, kidneys, lung, spleen, and brain (5, 6, 8, 9). Thus, blood GSH
reflected the whole body status.
A similar GSH and aging relationship occurs in humans. Healthy males and females from ages 20
to 94 years old were recruited from Louisville, Kentucky and their blood GSH status was
determined. Normal GSH concentration was determined in the 20- to 40-year-old subjects.
Reduced glutathione (GSSH) deficiency occurred in subjects older than 40 year and the number
increased with age, reaching as high as 50% of the 60- to 79-year-old age group (10).
GSH deficiency was also found in another group of elderly subjects in Michigan with an inverse
relationship between age and GSH level. In that epidemeologic study, GSH together with age and
measure of suppressed anger accounted for 39% of the variance of an index for morbidity (11).
The findings in healthy persons suggested an investigation of GSH in unhealthy subjects (12).
Newly admitted hospital patients who had a variety of major chronic diseases were consecutively
recruited along with healthy controls. Blood GSH levels were determined and correlated with their
diagnoses. Over 36% of the 74 patients were GSH deficient (P < 0.001).
At this time we became aware of reports that GSH was deficient in plasma and its cellular
components of HIV-seropositive subjects, regardless of CD4 lymphocyte level (13–17). Since Cys
is the rate-limiting precursor of GSH, its decrease inferred that Cys deficiency was the cause of
low GSH levels and implicated low levels of both GSH and Cys in the pathogenesis of HIV
infection. The importance of GSH and Cys to HIV infection has been well documented in these
articles.
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Drs. Richie and Lang, of the Department of Biochemistry, University of Louisville, were the first to
propose that a glutathione deficiency might be a biochemical cause of the aging process. They
demonstrated that glutathione levels decline with age in a number of organisms, including
mosquitoes, mice, and man. They proposed that restoring glutathione tissue concentrations to
those of younger organisms might result in an extension of the lifespan.
Our previous results indicated that a glutathione (GSH) deficiency is a determinant of the aging
process in many tissues and organisms. Correction of this deficiency in the aging mosquito by
feeding the cysteine (Cys) precursor magnesium thiazolidine carboxylic acid (MgTc) suggested
that the cause could be a lack of Cys.
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