Submitted by support on Sun, 04/22/2012 - 01:45
The effect of a patented nutritional supplement, MaxGXL, on lymphocyte intracellular glutathione levels and parameters of aging
Robert Keller MD, MS, FACP, AAHIVS Corresponding author: Robert Keller MD, MS, FACP, AAHIVS
ABSTRACT
Aim:
The primary objective of the study was to evaluate the safety, tolerability and efficacy of a proprietary nutritional supplement (MaxGXL) in promoting lymphocyte intracellular glutathione levels. The supplement, though not containing glutathione itself, is intended to raise intracellular glutathione levels by increasing biosynthesis/recycling and by decreasing glutathione consumption due to inflammatory oxidative stress. The secondary objectives included evaluation of changes in inflammatory markers and quality of life.
Methods:
The study was a randomized, double-blinded, placebo-controlled cross-over study with two arms involving 27 persons (9 male, 18 female) ranging from 31 to 72 years old. All participants received either 3 capsules of MaxGXL twice daily or placebo.
Subjects were followed for two months, then after a 14-day washout period, cross-over occurred and subjects were followed for an additional 2 months. At the end of the study, subjects were offered 1 month of open-label MaxGXL. Intracellular lymphocyte glutathione was determined using a kinetic enzymatic recycling assay on separated PBMC. Levels of IGF1, DHEA, and TNF α were measured.
Results:
Lymphocyte intracellular glutathione levels showed a progressive and significant increase over 2 months relative to baseline in subjects receiving the nutritional supplement. This increase was associated with decreased TNF α and increased levels of age-associated hormones (IGF1 and DHEA). All improvements increased sequentially over duration of study (month 2 > month 1) and no serious adverse events were observed.
Conclusions
: MaxGXL, a proprietary nutritional supplement, safely, effectively and significantly increases lymphocyte intracellular glutathione levels. The increases were progressive over the 2 month study period and were associated with decreased inflammation and improved levels of tested age-related hormones.
BACKGROUND
Glutathione
Glutathione (GSH) is a tripeptide composed of cysteine, glutamic acid and glycine. Of these, cysteine is of significant importance as it contains a sulfhydryl (SH) group, meaning that it can be oxidized by donating an electron. GSH is found in all cells and organs, but is particularly high in the liver and the spleen; the latter being composed predominately of T-lymphocytes. Although glutathione has multiple functions, including facilitating the transport of amino acids, detoxifying heavy metals, protecting cellular membrane integrity, regenerating Vitamin C, its major function appears to be antioxidation. 22
In fact, it is considered to be the most abundant and important intracellular low molecular weight sulfhydryl-containing peptide in mammalian cells, and one of the most important free radical traps in the human body. 7,11,32
Glutathione exists in two basic forms. The antioxidant form or “reduced glutathione” tripeptide is conventionally called “glutathione” or “ γ -L-glutamyl-L-cysteinyl glycine” and abbreviated as “GSH.” The oxidized form is a sulfur-sulfur linked compound known as glutathione disulfide (GSSG). It is ubiquitous in animals, plants and microorganisms and being water-soluble is found mainly in the cell cytosol and other aqueous phases of the living system. Glutathione often attains millimolar levels inside living cells, which makes it one of the most highly concentrated intracellular antioxidants. 4,7,11
Glutathione is homeostatically controlled, both inside the animal cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it per the gamma-glutamyl cycle 3.
It is most concentrated in the mammal liver (10mM), where the P450 Phase II enzymes
require it to convert fat-soluble substances into water-soluble GSH conjugates in order to
facilitate their excretion. While providing GSH for its efficient metabolic
functions, the liver parenchymal cells export GSH to the outside, where it serves as a
systemic source of -SH/reducing power.
Glutathione Depletion
Glutathione synthesis occurs within animal cells in two closely linked enzymatically
controlled reactions that utilize Adenosine Triphosphate (ATP) and draw on nonessential
amino acids as substrates. First, cysteine and glutamate are combined (by the enzyme
gamma-glutamylcysteine synthetase), with availability of cysteine usually being the ratelimiting
factor. Cysteine is generated from the essential amino acid methionine, from the
degradation of dietary protein, or from turnover of endogenous proteins. The buildup of
GSH acts to feedback-inhibit this enzyme, thereby helping to ensure homeostatic control
over GSH synthesis. The consequences of sustained GSH depletion are fatal. As cellular
GSH is depleted, first individual cells die in those areas most affected. Then zones of
tissue damage begin to appear. Localized free-radical damage spreads across the tissue in
an ever-widening, self-propagating wave. 17
As with other cell types, the proliferation, growth and differentiation of immune cells are
dependent on GSH. Both the T and the B lymphocytes require adequate levels of
intracellular GSH to differentiate, and healthy humans with relatively low lymphocyte
GSH were found to have significantly lower CD4 counts. 19
Intracellular GSH is also
required for the T-cell proliferative response to mitogenic stimulation, for the activation
of cytotoxic T “killer” cells, and for many specific T-cell functions, including DNA
synthesis for cell replication, as well as for the metabolism of interleukin-2, which is
important for the mitogenic response 17 and for the protection against Fas-mediated
apoptosis. 23
NrF2 regulates the sensitivity of death reception signals by affecting
intracellular glutathione levels 23
. In vitro glutathione supplementation enhances
interleukin-2 production and mitogenic response of peripheral blood mononuclear cells
from young and old subjects. 31
In summary, it has been demonstrated that decreased
levels of glutathione may be a result of various types of prolonged stress, increased free
radical formation and hyperactivity of the immune system. These factors in turn
compromise the health of mammalian cells.
There is a significant body of literature showing that plasma glutathione levels, as well as
intracellular glutathione levels, are directly related to outcome in diseases such as chronic
hepatitis
2, HIV infections28, various malignancies4 and malnutrition5
to name but a few.
In fact, any form of prolonged oxidative stress resulting in increased free radical
formation and/or hyperactivity of the immune system results in reduced glutathione
levels and resultant immunologic compromise. Despite the apparent importance of
maintaining glutathione levels, the literature regarding nutritional supplementation
remains controversial and no clear-cut mechanism for increasing plasma and/or
intracellular glutathione has emerged.
Plasma levels of glutathione have been demonstrated to be significantly decreased in
conditions as diverse as malnutrition 5
, various infections including HIV and Chronic
Hepatitis
2,28and a wide variety of malignancies4
(see Figure 1). However, no causal
relationship has been proven between the low glutathione levels and disease. Despite this,
there is no clear-cut consensus on an efficient and consistent methodology to increase
plasma GSH and, more importantly, intracellular GSH by nutritional supplementation.
Both intravenous and intrapulmonary installations of GSH have been used to
reverse/protect hepatotoxicity in acetaminophen poisoning
9
, but parenteral administration
is impractical due to both cost and inconvenience. As a result, the literature is rife with
studies of oral supplements. In general, these have involved the use of cysteine
(predominantly as N-acetyl cysteine) or the use of oral glutamine. The difficulties
attendant with disturbed digestive functions in chronic debilitating conditions and the
finding that elevated plasma glutamate levels (which occur in chronic conditions) can
both inhibit cysteine uptake by cells as well as directly inhibit GSH synthesis, have
limited the utility of oral supplementation in patients with chronic viral infections and
malignancies.
12
Correction of Glutathione Depletion
Studies have demonstrated that oral glutathione is not well absorbed by many of the
mammal’s cells and does not replenish losses inside cells where it is most needed. 29
The
sulfur-containing amino acid L-cysteine is the precursor that most limits cellular
biosynthesis of GSH. When substituted into the diet in place of the total protein
allowance it was effective in raising GSH levels. 29
Glutathione esters are synthetic
compounds prepared by linking the glycine end of GSH into ester bonds. 21,22
These esters
do appear to be effective GSH delivery vehicles, but have the disadvantage that they
yield alcohols in vivo when their ester bonds are broken, and their safety over the long
term has yet to be satisfactorily demonstrated.
Studies suggest that to efficiently raise the levels of glutathione intracellularly, it is
necessary to employ several different mechanisms that work simultaneously. First,
essential elements needed by the body for manufacture of glutathione must be introduced.
Second, gastrointestinal health of the mammal must be able to facilitate nutrient
absorption. Third, the liver function must be supported and protected, as the liver is the
glutathione “manufacturing and storage house.” Fourthly, it is advantageous to support
recycling of existing glutathione and enhancing enzymatic reactions that promote
glutathione synthesis. In addition to promoting glutathione synthesis and recycling,
another mechanism of improving glutathione concentration is to reduce its ancillary
utilization as a free radial trap, thereby preserving it for use as a reluctant for the
oxidation reactions which are necessary for the mitochondrial production of ATP in every
mammalian cell.
MaxGXL
The present study tested the ability of a complex nutritional supplement, MaxGXL to
raise intracellular glutathione levels and counter certain metabolic correlates of aging.
This proprietary nutritional supplement represents a novel amalgam of glutathione
promoting methodologies. It contains phytocyanins (facilitators of digestive absorption),
N-acetyl cysteine (which releases cysteine, the rate-limiting component for glutathione
biosynthesis), promoters of glutathione recycling and cordyceps.
Cordycepin, the active ingredient in Cordyceps sinensis (and other species) 20,24
has
many demonstrated functions including anti-tumor, neuroprotective, and hypoglycemic
effects. Its functions of import in preserving glutathione are its anti-inflammatory,
immunomodulatory, antioxidant and hypolipidemic effects. Cordycepin enhances
hepatic metabolism and ATP production, 6
thereby enhancing hepatic glutathione
production.
The anti-inflammatory activity of cordyceps is based upon reduction of nuclear factor
kappa beta (NF κB) activity in macrophages. Decreased NFκ B activity diminishes
macrophage activation leading to decreased production of proinflammatory cytokines
(including IL
1, IL6 and TNFα
) and intra and extracellular free radicals. The antiinflammatory
action of cordyceps increases glutathione levels because inflammation
produces free radicals, reactive oxygen and reactive nitrogen species which damage
cellular components unless they are neutralized by antioxidants, such as glutathione.
Glutathione is the most prevalent antioxidant in cells, reaching millimolar concentrations
in some tissues such as the liver. 11,7 In the liver, glutathione can explain nearly 50% of
the total reactive antioxidant potential of the tissue. 11
In quenching reactive species, glutathione becomes oxidized and is exported from the
cell, therefore decreasing the intracellular concentration of glutathione. Reduced
glutathione is crucial because it is required for the regeneration of all other antioxidants.
This is important because it is the only natural antioxidant whose oxidation does not
produce free radicals. The attenuation of inflammation, therefore, promotes enhanced
levels of total and reduced glutathione in cells.
In summary, MaxGXL is expected to increase glutathione concentrations by promoting
gastrointestinal absorption of the precursors, facilitating intracellular transport of the
requisite components, promoting intracellular glutathione synthesis, and recycling
oxidized glutathione. It may protect intra- and extracellular concentrations of glutathione
by enhancing hepatic metabolism and reducing ancillary glutathione utilization by
reducing macrophage-induced inflammation, the production of proinflammatory
cytokines, and ultimately reducing free radical production. In this way, it may preserve
glutathione for its role in facilitating increased cellular energy through enhancing
mitochondrial ATP production.
Glutathione and Aging
Glutathione depletion may also play a significant role in aging, at least in part through its
role as a major protector of mitochondrial DNA (MtDNA). Maintenance of normal
MtDNA directly correlates with maximum life span, which has been estimated at 122
years in humans. 1
During ATP production in the mitochondria, superoxide free radicals
are produced which are converted to hydroxyl and peroxide free radicals. GSH
neutralizes hydroxyl free radicals and is an essential component of GSH peroxidase,
which neutralizes peroxide free radicals. These free radicals generated within the
mitochondria have the potential to damage MtDNA. At age 90 only 5% of normal
MtDNA remains when compared to the normal MtDNA level of a 5 year old. GSH levels
decrease with age (1% per year) which may account for at least some of the cumulative
MtDNA damage.
Promoting high levels of reduced mitochondrial glutathione may counter some of the
effects of aging. It has been found that centenarians demonstrate GSH levels similar to
30-50 year old well normals, suggesting that their atypical GSH levels have been pivotal
in preserving their health. In support of this notion, it has been found that caloric
restriction, which prolongs life, increases both the aging–associated deacetylase Sirtuin1
and GSH levels.
Glutathione may play a significant role in aging. Raising intracellular glutathione levels
may reduce the metabolic signs of aging and protect mitochondrial function.
METHODS
Participants
Recruitment was from patients of the KBK Institute of Advanced Medicine, MaxGXL
distributor-derived subjects, and newspaper advertisement. Subjects lacked allergy to any
of the ingredients of MaxGXL (including mushrooms, shellfish and Silimarin) and did
not use glutathione or glutathione-producing supplements within 2 weeks of baseline, nor
did they participate in any experimental study within 1 month of baseline.
This study was approved by the Independent Institutional Review Board. The purpose,
nature, and potential risks of the study were explained to all participants, who gave their
written informed consent before participation. The study was conducted in accordance
with the U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and
21 CFR including parts 50 and 56 concerning informed consent and IRB regulations) and
in full conformity with the current revision of the Declaration of Helsinki, or with the
International Conference for Harmonization Good Clinical Practice (ICH-GCP)
regulations and guidelines, whichever afforded the greater protection to the subject.
Cordyceps may prolong pro-thrombin time, so subjects on warfarin-like anticoagulants
were excluded. All participants had prothrombin time and partial prothrombin time
within normal limits. Because vitamin C and alpha lipoic acid can cause mild heartburn,
subjects with gastroesophageal reflux disease, severe heartburn, esophageal varices or
beta-blocker dependent cirrhosis were excluded. Additionally subjects were free of
treatment or diagnosis of congestive heart failure, senile dementia, Alzheimer’s or multiinfarct
dementia, peptic ulcer, or end stage renal disease. Subjects were excluded who
had diagnosis or treatment of cancer within 6 months of the study, except basal or
squamous cell skin cancer. Subjects with diagnosis or treatment for chronic illness
without definitive diagnosis were excluded.
The women of childbearing potential were neither pregnant nor lactating. Participants
agreed to limit alcoholic beverages to 2 per day for men and 1 per day for women, as well
as to abstain from all Tylenol products unless deemed medically necessary.
Subjects were substance abuse free for a minimum of 6 months prior to baseline, and those on
prescribed narcotics were at steady state for a minimum of 3 months prior to onset of
baseline. Participants did not use antibiotics for more than 10 days within 1 month of
baseline.
Study Design
The study was a randomized, double-blinded, placebo-controlled cross-over study with
two treatment arms. A total of 27 subjects (9 males, 18 females) were enrolled (age range
31-72). Subjects were assigned on a random basis to the active treatment arm or to the
placebo treatment. Randomization was prepared by the manufacturer which provided
MaxGXL and placebo as numerically labeled bottles. All study participants remained
blinded to the randomization assignment for the duration of the study. Subjects consumed
3 capsules twice a day. Follow up visits occurred at one and two months. After two
months, there was a 14-day washout period before the cross-over. In a double-blinded
fashion, subjects previously receiving MaxGXL were issued placebo and subjects
previously receiving placebo were issued MaxGXL. Additional follow-+up visits
occurred at one and two months after the cross-over. At the conclusion of the cross-over
period, and at the subject’s sole discretion, all subjects were offered one month of open
label MaxGXL. A follow up visit was scheduled after one month. At the final study visit,
or in the case of an early discontinuation visit, volunteers were given a final interview.
Blood was obtained at screening, 1 month and 2 months of follow up, and the end of the
washout period. After the cross-over, blood was obtained at 1 month, 2 months and at the
final study visit. Subjects were asked about any problems which occurred while on the
experimental product or comparator and any health problems or changes in their health.
Less than 80% compliance by patient report was considered a protocol violation.
All laboratory values were compared at initiation and monthly for two months. Safety
parameters were noted including clinical laboratory, adverse events, and medical history.
Volunteers were asked to promptly report possible side effects, illnesses, infections,
medical problems, surgeries, missed doses, lost study products, and other life problems
affecting their compliance. Reported side effects were specifically evaluated during the
study. Side effects data therefore was not blinded but was collected primarily for safety
analysis.
Supplement
Both MaxGXL and placebo were obtained from the manufacturer, who provided them in
coded bottles. The dosage was 2 daily servings of 3 capsules. Three capsules contain 250
mg vitamin C as Calcium Ascorbate USP, 750 mg L-Glutamine, 375 mg N-Acetyl
Cysteine (NAC), 75 mg Alpha Lipoic Acid, and 488 mg of a proprietary GSH Absorption
& Recycling Blend consisting of Cordyceps, N-Acetyl D-Glucosamine, Quercetin, Milk
Thistle (Silybum marianum) Extract containing 80% Silimarin. Placebo was also
administered as 3 capsules BID.
Laboratory Evaluation
The following blood tests were performed by LabCorp or KBK Institute of Advanced
Medicine; CBC, ESR, Comprehensive Chemistry, PT, PTT, Lymphocyte Glutathione, IL
1 IL6, TNF Alpha, Cystatin, Fasting Insulin, Cortisol, DHEA, IGF1, testosterone (men
only), progesterone (women only) and estradiol levels. Total lymphocyte intracellular
glutathione was determined using a kinetic enzymatic recycling assay kit from Oxford
Biomedical Research on separated PBMC. PBMC were separated using Cell Preparation
Tubes (Becton Dickinson), and immediate processing within 30 minutes using ice-cold,
5% metaphosphoric acid. Cortisol, estradiol, progesterone and testosterone levels were
determined using an Immulite 2000 system.
Statistical Methods and Data Analysis
Efficacy as related to lymphocyte glutathione was evaluated at each time point relative to
baseline. DHEA, Igf1, and TNF alpha were compared between groups at each time point
using a two-tailed t- test.
The safety endpoint data was summarized for the study
population. Statistical analysis was performed to estimate the treatment effect of
MaxGXL and placebo control using participants’ two-tail t-test with significance
assigned at a p<0.05 values.
RESULTS
Intracellular lymphocyte glutathione
Normal subjects receiving the nutritional supplement designed to raise glutathione levels
demonstrated a 121% change from baseline levels in lymphocyte intracellular glutathione
over 1 month (p<0.01). The range after 1 month was from 72 to 154 nanograms/10 6 cells.
Glutathione levels increased further over 2 months to 276% change (p<0.001). The range
after 2 months was from 155 to 310 nanograms/10 6 cells. In contrast, the glutathione
level of participants receiving placebo decreased -3% over 1 month (p<0.05) and -7 %
over 2 months (p<0.05). The ranges were from 1 to 9 nanograms/10 6 cells and from 3 to
15 nanograms/10 6 cells, respectively. Three subjects with chronic insomnia showed the
least improvement.
Figure 2.
Increase in Intracellular Lymphocyte Glutathione Levels
using a Patent Pending Oral Glutathione Optimizer.
1 month 2 months P < 0.01 P < 0.001 P < 0.05 P < 0.05
Age-associated hormone levels
Progressive improvements in age-associated hormone levels were observed in normal
subjects receiving the glutathione promoting supplement. After 1 month, there was a 16%
change from baseline in IGF1 levels (p<0.05). The range was 6 to 41 ng/mL. After the
second month of supplementation, there was a 41% change in IGF1 levels (p<0.001). The
range was from 14 to 80 ng/mL. The decreases in IGF1 levels in placebo-treated subjects
were not statistically significant (-3% at 1 month and -8% at 2 months). The ranges were
from 1 to 5 and from 3 to 11 ng/mL, respectively.
Similarly the age-associated hormone DHEA also increased in subjects receiving the
glutathione promoting supplement. After 1 month, there was an 18% change from
baseline in DHEA levels (p<0.05). The range was 6 to 33 ng/dL. After the second month
of supplementation, there was a 46% change in DHEA levels (p<0.001). The range was
from 18 to 52 ng/dL. The changes in DHEA levels in placebo treated subjects were not
statistically significant (-2 at 1 month and -6 at 2 months). The ranges were from 0 to 5
and from 3 to 11 ng/dL, respectively.
Inflammation Marker
The glutathione-promoting supplement lowered levels of markers of inflammation. The
inflammatory cytokine TNF α decreased progressively from baseline at 1 and 2 months
(from -41 to -61 % change). These changes were highly significant (p<0.001 and
p<0.0001 respectively). The decrements ranged from -14 to -54 pg/ml at 1 month and -27
to -94 pg/mL at 2 months. Of 25 subjects, 19 showed decreased levels of the
proinflammatory cytokine. In the placebo controls, in contrast, TNF α levels increased. At
1 month the controls had a nonsignificant 4 % change and at 2 months the percent change
was 6 (p<0.05). The increment ranged from 2 to 11 and from 6 to19 pg/mL. Note that
the TNF α assay is only sensitive to 6 pg/ml so the percent change may be underestimated.
Figure 4.
Improvement in Markers of Inflammation using a Patent Pending Oral Glutathione Optimizer
Safety
Subjects were queried at each visit about health problems or changes in their health. No
serious adverse events were reported by the subjects.
DISCUSSION
The proprietary nutritional supplement, MaxGXL, safely raised lymphocyte glutathione
levels in normal subjects in a placebo-controlled, double-blind study. This supplement
does not contain glutathione itself but rather promotes the cellular synthesis of
glutathione and reduces its consumption by decreasing inflammation. The increase in
glutathione levels was associated with increases in the hormones IGF1 and DHEA, which
normally diminish during the aging process. In concert with these changes, decreases
were observed in the marker of inflammation TNF α .
Other benefits of raising the levels of glutathione relate to quality of life. Oxidized
glutathione (GSSG) induces sleep. The effects of improved sleep include improved
mood, energy, mental focus and decreased pain.
This study is limited by the small number of patients and the short term.
Given the progressive nature of the improvements in glutathione, IGF1, DHEA, and
TNF α , the question remains whether expanded, longer-term studies would show
sequential improvements. The results suggest strongly that such studies are warranted,
given the wide variety of diseases associated with decreased glutathione levels.
This research was supported in part by KBK Institute of Advanced Medicine.
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