EDITORIAL
Glutathione: A marker and antioxidant for aging
Abbreviations: GR ⫽ glutathione reductase; GSH ⫽ reduced glutathione; GSSCy ⫽ mixed
disulfide with cysteine; HPLC ⫽ high-pressure liquid chromatography; SOD ⫽ superoxide
dismutase
A
ging individuals form an ever increasing per-
centage of the population, and the mainte-
nance of quality of life in later years utilizes
a significant proportion of the nation’s medical mone-
tary expenditures. In the etiology of aging, Parkinson’s
disease, Alzheimer’s disease, amyotrophic lateral scle-
rosis, trauma, and other diseases, oxidative stress has
been implicated.1 Oxidative stress implies imbalance in
the neutralization of oxygen related free radicals (eg,
superoxide anion [O2⫺●], hydroxyl [OH●], and nitrogen
dioxide [NO2●]). As a consequence, there is enhance-
ment in the deleterious effects of these radicals on
cellular functions. The body has multiple antioxidant
defenses, of which SOD and GSH seem especially
important. GSH scavenges free radicals and is con-
verted to GSSG or GSSCy which is reduced back to
GSH by the enzymatic activity of GR. GSH protects
cells from oxidative stress. The detoxification capabil-
ity of GSH is directly related to its reduced thiol group.
The enzymatic activity of glutathione-peroxidases and
glutathione-transferases is also dependent on reduced
thiol group of GSH. GSH and other reduced thiols are
important for the ability of the body to resist oxidant
stress. It has been postulated that decreased levels of
reduced GSH would be a marker for increased suscep-
tibility to oxidant injury and also indicating depletion of
From the Mayo Clinic.
Submitted for publication August 14, 2002; accepted August 20,
2002.
Reprint requests: Ravinder J. Singh, PhD, Mayo Clinic, Hilton 730,
200 1st Street SW, Rochester, MN 55905; e-mail:
singh.ravinder@mayo.edu.
J Lab Clin Med 2002;140:380-1.
Copyright © 2002 by Mosby, Inc. All rights reserved.
0022-2143/2002 $35.00 ⫹ 0 5/1/129505
doi:10.1067/mlc.2002.129505
380
reserves due to oxidative stress. The use of GSH as an
anti-aging drug has recently increased remarkably, but
this use is unsubstantiated by clinical data. GSH ho-
meostasis has been reported to be altered in a wide
variety of human diseases. In order to understand the
mechanism of its action, the measurement of the steady
state levels of GSH and the rate of synthesis of GSH
has been reported in various diseases.
In a study of 176 healthy individuals negative corre-
lations were observed between age and GSH, GSH/
GSSG molar ratio or GR activity.2 There were positive
correlations between age and glutathione-peroxidase
and GSSG levels. A different study of 74 patients with
chronic illnesses reported that one third of these pa-
tients had GSH levels below the lower limit of normal
and GSSG levels were similar to those in control sub-
jects. In another study the GSH levels in 60-79 year old
group were 17% lower than the reference group.3 In a
representative study of community-based elderly group
(N ⫽ 33), higher glutathione levels were associated
with fewer illnesses, better self-rated health, lower cho-
lesterol, lower body mass index, and lower blood pres-
sures.4
In the current issue of Journal, a study by Lang et al5
reports that GSH status in non-diseased aged individu-
als with better psychosocial or mental health is similar
to healthy young individuals. The conclusion of the
study is that total GSH levels in whole blood correlated
very well with the physical health irrespective of the
age. According to the study, the well-being of healthy
females ⬎ 60 years old can be predicted by their GSH
levels. This is an important finding and needs to be
supported by other studies that monitor the levels of
reduced GSH and GSSG in elderly populations. Studies
like these are difficult to complete and require a lot of
planing and resources to validate the hypothesis. There-
fore the selection of patient population, endpoints,
J Lab Clin Med
Volume 140, Number 6
methods of analysis, and biochemical markers of oxi-
dative stress that are compatible with the hypothesis is
very crucial. All these are necessary for the validation
of the hypothesis that minimal GSH levels are indis-
pensable in aging and various other diseases. Recent
improvements in technology enable the development of
methods that precisely and accurately measure reduced
GSH concentrations in humans. In the analysis of blood
or serum samples, the fractionation of GSH and GSSG
concentrations is essential in understanding the role of
reduced GSH in aging and other diseases. Recently, the
use a novel approach of estimation of redox potential of
GSH has suggested that in age-related pathologies,
oxidation of GSH may be more important in aging than
a decrease in total GSH.6 But in specific diseases such
as diabetes, both oxidation and a deficiency in total
GSH may be observed.
For quantitative analysis of reduced GSH, enzymatic,
spectrophotometric, fluorometric, and HPLC-based
methods have been used in numerous reports and all of
these methods have used derivitization of GSH and
GSSG. These reports lack validation and method com-
parison data and don’t help in the selection of the best
method for use in clinical laboratories. HPLC methods
with various detectors (eg, ultraviolet, fluorometric, and
electrochemical detection) have been developed and are
relatively more specific.7 The recent invention of elec-
trospray interface, enabling the coupling of HPLC to
mass spectrometers, has helped in the development of a
method with increased specificity and sensitivity in
comparison to the spectrophotometric- or fluorescence-
based detection methods. State of the art tandem mass
spectrometers offer several advantages over single
stage instruments, which can target molecular ions of
Editorial 381
GSH and GSSG in the first mass analyzer and a char-
acteristic fragment of GSH and GSSG in the second
mass analyzer offering greater specificity.8 Further
studies in large different populations with a uniform
method of quantitation of GSH are needed to support
that GSH is a potential health risk factor for morbidity
among the aging population.
RAVINDER J. SINGH
Mayo Clinic
Rochester, Minn
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