Recent Advances on the Nutritional Effects Associated with

the Use of Garlic as a Supplement

Aged Garlic Extract, a Modulator of Cardiovascular Risk Factors:

A Dose-Finding Study on the Effects of AGE on Platelet Functions1
M. Steiner2 and W. Li
Division of Hematology/Oncology, East Carolina University School of Medicine, Greenville, NC 27858-4354

KEY WORDS: organosulfur compounds

cardiovascular risk factors

aged garlic extract

Cardiovascular disease remains the foremost cause of death

in developed countries even though a steady decline in mortality and morbidity has been recognized over the past few
decades. Much of this decline is due to an effort to reduce
hypercholesterolemia, a major risk factor for this group of
diseases. Effective treatment of hypertension, another major
risk factor, has also contributed to the decline. Of great importance as well are advances in the treatment and prevention
of myocardial infarctions using a variety of techniques both
medical and surgical. There has been an increasing recognition that certain natural substances have the potential to
reduce the detrimental effect of a number of cardiovascular
risk factors. By and large, the efficacy of such biofactors lags
behind pharmaceutical intervention in the amelioration of the

platelet aggregation

platelet adhesion

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ABSTRACT Aged garlic extract (AGE) has been shown previously to have moderate cholesterol-lowering and
blood pressurereducing effects. We have now investigated whether platelet function, a potential risk factor for
cardiovascular disease, can be inhibited by AGE administration. In a randomized, double-blind study of normal
healthy individuals (n 34), both men and women, the effect of AGE was evaluated in doses between 2.4 and 7.2
g/d vs. equal amounts of placebo. Platelet aggregation and adhesion were measured at 2-wk intervals throughout
the study. Threshold concentrations for epinephrine and collagen increased moderately during AGE administration
compared with the placebo and baseline periods. Only at the highest supplementation level did AGE show a slight
increase in the threshold level of ADP-induced aggregation. Platelet adhesion to collagen, fibrinogen and von
Willebrand factor was investigated by perfusing whole blood through a laminar flow chamber under controlled flow
conditions. Adherence of platelets was inhibited by AGE in a dose-dependent manner when collagen was the
adhesive surface perfused at low shear rates (30 s1). At high shear rates (1200 s1), AGE also inhibited platelet
adhesion to collagen but only at higher intake levels. Adhesion to von Willebrand factor was reduced only at 7.2
g/d AGE, but adherence to fibrinogen was potently inhibited at all levels of supplementation. Thus, AGE exerts
selective inhibition on platelet aggregation and adhesion, platelet functions that may be important for the
development of cardiovascular events such as myocardial infarction and ischemic stroke. We briefly review the
effect of garlic preparations in general on cardiovascular risk factors and point out differences between AGE and
other garlic preparations that we feel are important to explain the efficacy of AGE. J. Nutr. 131: 980S984S, 2001.

prevalence of risk factors. Their primary use lies in the field of

prevention, i.e., before the occurrence of major cardiovascular
events such as myocardial infarction or strokes as caused by
cerebrovascular disease. The use of natural substances has
become more widespread over the past few years, driven undoubtedly by the belief that natural substances may have fewer
side effects than do pharmaceuticals and by their ready availability to the public without prescriptions or visits to health
providers.
Garlic and various forms of extracts prepared from it represent an example of such natural substances that have been
claimed to possess beneficial effects for the prevention of
various aspects of cardiovascular disease. Although a large
number of intervention trials have been reported in the literature, most studies have been small. Meta-analyses (Silagy and
Neil 1994, Warshafsky et al. 1993), which combine the data of
many of the intervention trials, have sought to arrive at
conclusions about the efficacy of the preparations. However,
because of the different nature of the supplements used in
these studies, the relatively short time of their administration
in most trials and the widely varying characteristics of the
study populations, it is difficult to draw definitive conclusions.
We report here the results of a recently completed dose-

1
Presented at the conference Recent Advances on the Nutritional Benefits
Accompanying the Use of Garlic as a Supplement held November 1517, 1998
in Newport Beach, CA. The conference was supported by educational grants from
Pennsylvania State University, Wakunaga of America, Ltd. and the National
Cancer Institute. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors: John Milner, The Pennsylvania
State University, University Park, PA and Richard Rivlin, Weill Medical College of
Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY.
2
To whom correspondence should be addressed. E-mail:
steiner@brody.med.ecu.edu.

0022-3166/01 $3.00 2001 American Society for Nutritional Sciences.

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finding study on the effect of aged garlic extract (AGE), a

garlic preparation composed primarily of stable components
derived from those present in fresh garlic, on platelet function.
The results of an intervention trial using a large supplement
dose of AGE in a group of moderately hypercholesterolemic
men were reported previously (Steiner et al. 1996). Major
findings of our study were AGE-induced reduction of platelet
aggregation in response to collagen and epinephrine and a
reduction of platelet adhesion to collagen and fibrinogen, but
not to von Willebrand factor. Measurement of S-allylcysteine
(SAC) levels in the blood not only provided evidence of
compliance but also showed that at least one of the major
constituents of AGE was absorbed from the human intestine.
Experimental design and methodology. We recruited a
group of normal individuals (n 34), both men and women,
who were in good physical health, to this 44-wk long, doubleblind, crossover study. After an initial 6-wk baseline period
during which no supplements were administered, the study
participants were randomly selected to receive either AGE or
placebo in a dosage of 3 capsules/d (each 800 mg) for a period
of 6 wk. After this 6-wk period, the dosage was raised to 6
capsules/d for 6 wk, and finally to 9 capsules/d for another 6
wk. The first intervention period was followed by a 2-wk
washout period. The subjects were then switched to the other
supplement that they did not receive during the first arm of the
study. A final 2-wk washout period concluded the study. The
study was completed by 28 of 34 individuals enrolled. Reasons
for dropping out of the study included complaints of gastrointestinal problems, such as heartburn, flatulence, complaints of
body odor and allergy. One individual was terminated because
of overt noncompliance; another had to stop because of relocating to another area of the state.
Blood was sampled every 2 wk and processed for platelet
aggregation and adhesion studies. Aliquots of plasma were
stored at 80C, some for use as yet to be determined, and
others for measurement of SAC levels.
Platelet function studies. Whole blood (50 mL) was collected in 0.1 volume of 3.8% sodium citrate in normal saline.
For platelet aggregation studies, platelet-rich plasma was prepared by previously described methods (Landolfi et al. 1984).
Aggregation was tested with the following agonists: arachidonic acid, ADP, collagen and epinephrine. Each platelet
stimulant was used in a range of concentrations to determine
threshold levels for each agonist capable of inducing complete
aggregation, which signifies achievement of 80% maximal
aggregation. Platelet aggregation was determined in a multichannel aggregometer. Maximal aggregation and initial slope
were two parameters analyzed by the instrument.
Measurement of platelet adhesion. The adherence of
platelets to collagen-, fibrinogen- and von Willebrand factor
coated surfaces was evaluated in a Hele-Shaw type laminar
flow chamber perfused with whole blood at shear rates of either
1200 s1 or 30 s1. The low shear rate perfusion was used
only with collagen-coated surfaces. The characteristics of the
flow chamber and the experimental set-up have been described
previously (Jandak et al. 1989). Whole blood was perfused
through the flow chamber under temperature-controlled conditions (37C) for 10 min. Washing procedures as well as
quantitative analysis of the adherent platelets have been described (Steiner and Lin 1998). Adhesion studies to fibrinogen- or von Willebrand factor coated surfaces were performed
in two different subsets of the study population, n 17 and n
11, respectively. Both of these adhesion measurements were
done at a high shear rate (1200 s1).
Statistical analysis. Threshold concentrations of individual agonists were used for comparison. Aggregation data using

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FIGURE 1 Evaluation of threshold concentrations for three different platelet agonists, (A) epinephrine, (B) ADP and (C) collagen. Means
1SEM are presented for baseline period (BL), three different aged
garlic extract (AGE) supplementation periods, i.e., 3 (2.4 g), 6 (4.8 g) and
9 capsules/d (7.2 g), washout period (WP) and three placebo periods of
3, 6 and 9 capsules/d. *Significantly different (P 0.05) compared with
baseline and placebo values.

arachidonic acid as platelet stimulant were analyzed solely to

determine whether the study subjects had ingested nonsteroidal anti-inflammatory agents, inhibitors of platelet cyclooxygenase. Group means were compared by ANOVA using the
statistical software program SPSS (Chicago, IL).
RESULTS
Platelet aggregation. Aggregation studies using ADP as a
stimulant showed a minimal increase in the threshold concentration in individuals consuming AGE (Fig. 1B). Compared
with the baseline and placebo arms of the study, threshold
levels during AGE administration increased from between 4.5
and 5.2 mol/L to 6.17.1 mol/L. This increase was significant only at the highest intake level, i.e., 7.2 g AGE/d (P
0.05). There was no significant difference between supplementation levels of AGE (i.e., 2.4 and 7.2 g/d).

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FIGURE 2
Platelet adhesion to
(A, C) collagen-, (B) von Willebrand
factor and (D) fibrinogen-coated surfaces. Adhesion to collagen-coated
surfaces was conducted at shear rates
of (A) 30 s1 and (C) 1200 s1. Means
1SEM of baseline, placebo, washout,
and aged garlic extract (AGE) supplementation periods with 3, 6 and 9 capsules/d are shown. *Significantly different (P 0.05) compared with baseline
and placebo period measurements;
**significantly different, P 0.01. For
adhesion measurements to collagen, n
28; n 11 for von Willebrand factor
and n 17 for fibrinogen-coated surfaces.

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Collagen-induced aggregation, on the other hand, showed a

significant rise in threshold doses after administration of AGE
(Fig. 1C). Threshold levels for this agonist ranged between
0.41 and 0.52 g/mL at baseline and during placebo administration. After AGE, the threshold levels increased to 0.82
g/mL at an intake level of 2.4 g AGE/d and rose to 1.1 g/mL
when intake was raised to 4.8 g/d. There was no further change
when the supplementation was increased to 7.2 g/d. At all
three supplementation levels, the aggregation responses were
significantly different from those under baseline and placebo
conditions.
Platelet aggregation induced by epinephrine (Fig. 1A) was
also inhibited by AGE. With consumption of 2.4 g AGE/d, the
threshold level for this agonist increased significantly from
between 4 and 4.4 mol/L to 6.5 mol/L. Further increase of
AGE supplementation did not produce a significant enhancement of AGE-induced inhibition. In fact, at high doses (7.2 g
AGE/d) the threshold concentration was not significantly
different from that of baseline or placebo-supplemented
groups.
Platelet adhesion. Adhesion to collagen-coated surfaces
was examined in all study participants (Fig. 2A, C). Two
different shear rates were investigated. At low shear rates
(30 s1) (Fig. 2C), there was a small but significant reduction in platelet adhesion when 4.8 7.2 g AGE/d were consumed. At a daily dosage of 2.4 g AGE/d, no significant
reduction of platelet adherence was noted. The maximal reduction obtained at the higher supplement levels was 25%
below that of baseline or placebo-supplemented groups. High
shear rate adhesion (1200 s1) to collagen (Fig. 2A) showed a
progressive decline with escalating AGE dosage. Compared
with low shear rate adhesion, fewer platelets adhered to the
collagen-coated surface. The maximal reduction was 50%,
which was obtained in individuals supplemented with 7.2 g
AGE/d.
Adhesion to fibrinogen (Fig. 2D) and von Willebrand factor (Fig. 2B) were both measured in a subgroup of the study
population. The former was significantly inhibited by AGE at
all concentrations used, slightly more at intake levels of 4.8
and 7.2 g than at 2.4 g/d. Even at the last-mentioned dosage,
however, adhesion was reduced by 33% compared with
baseline or placebo groups. Although the higher concentra-

tions of AGE, i.e., 4.8 and 7.2 g/d, resulted in an increase in

inhibition of 10% over that achieved with 2.4 g AGE, the
difference among the three intake levels of AGE was not
significant. Adhesion to von Willebrand factor coated surfaces was reduced only at the highest intake level (7.2 g/d).
The reduction was 33% compared with baseline or placebo
groups.
Correlation of serum SAC levels with dietary intake of
AGE. Measurement of serum SAC levels was done in a
majority of the study participants. One study subject who
showed overt noncompliance and was eventually eliminated from the study failed to show any increase in SAC.
All other individuals consuming AGE exhibited an increase in SAC level that peaked when they were consuming
4.8 g/d (Fig. 3). It was interesting to note that placebo
administration also produced an increase in SAC levels that
was progressive with dose escalation. The differences compared with baseline, however, were not significant. After
stopping AGE supplementation, i.e., during the washout
period, there was a sharp drop in SAC levels in all study
subjects.

FIGURE 3 Evaluation of serum S-allylcysteine (SAC) levels of 27

study participants. Means 1SEM of baseline, three different supplementation levels of aged garlic extract (AGE) (3, 6 and 9 capsules/d),
washout period and placebo administration period are shown. *Significant difference between baseline and placebo periods, P 0.05.

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DISCUSSION

tion again provided little (for collagen only) if any greater

inhibitory effect than lower levels of AGE intake (2.4 g/d). As
with aggregation studies, there was specificity of inhibition of
platelet adhesion. With the use of fibrinogen- and collagencoated surfaces, significant reductions were observed, but not
with von Willebrand factor coated surfaces. Using similar
reasoning as for platelet aggregation leads to the suggestion
that individual receptors for these adhesive proteins may be
affected differently by AGE supplementation. Although adequate for aggregation, the washout period of 2 wk was clearly
not sufficient in length to evaluate the effect of AGE on
platelet adhesion.
The efficacy of AGE as a means of reducing other cardiovascular risk factors, such as total and LDL cholesterol levels
and blood pressure, was investigated in our previous study
(Steiner et al. 1996) in which the effect of a prolonged
supplementation (6 mo) with AGE was evaluated. A few
meta-analyses have been published (Silagy and Neil 1944,
Warshafsky et al. 1993) that summarized the diverse data base
on garlic-induced alterations of lipid profiles. Notwithstanding
the negative results of recent studies using non-AGE garlic
extracts, i.e., dehydrated garlic powder or garlic oil products
(Berthold et al. 1998, Issacsohn et al. 1998), the majority of
the published intervention trials provided evidence of a modest but significant reduction (8 11%) in total and LDL
cholesterol levels in the blood. The magnitude of the changes
observed makes it clear that small-scale studies, such as those
reported to date, will be unable to give definitive answers on
the health benefits of the preparations when evaluated individually. The situation with this dietary supplement is similar
to that of other dietary manipulations that have been studied
for their effect on lipid profiles. It is important to recollect that
definite conclusions about effectiveness could be obtained only
after pooling large numbers of studies to achieve the statistical
power required to define significance. These remarks also apply
to the inhibition of platelet function by dietary supplements
and even pharmaceutical platelet inhibitors.
It should be pointed out that several of the water-soluble
compounds present in AGE such as SAC, S-ethyl cysteine,
and S-propyl cysteine quite potently inhibit cholesterogenesis
by cultured hepatocytes of rats in vitro. A 40 60% inhibition
of acetate incorporation into cholesterol and fatty acids was
observed (Yeh and Yeh 1994). Lipid-soluble organosulfurs
such as diallylsulfide, diallyldisulfides and diallyltrisulfides, as
well as dipropylsulfide, dipropyldysulfide and methylallylsulfide
also decrease cholesterol synthesis of hepatocytes but only by
10 15% and by damaging the cells as evidenced by release of
cellular lactate dehydrogenase (Yeh and Liu, 2001). Thus, the
inhibition of cholesterol synthesis by lipid-soluble compounds
may be a result of cytotoxicity, whereas the inhibition by
water-soluble compounds appears to be the result of metabolic
alterations.
The difficulty of evaluating natural substances that are
prepared in a variety of ways is clearly demonstrated for garlicrelated extracts. For AGE, detailed investigations in vitro, ex
vivo and in vivo have shown that this supplement is absorbed
from the intestinal tract and at least one major biologically
important component, SAC, can be measured in the blood.
This has not or could not be done with other garlic extracts
currently on the market. Freeman and Kodera (1995) demonstrated that allicin, one of the most effective organosulfurs of
fresh garlic in vitro, which also forms the basis of most potency
measurements of preparations made from fresh garlic, shows
rapid destruction in the blood. It appears to interact with the
iron in hemoglobin, oxidizing it to the trivalent form, thus
producing methemoglobin. Furthermore, although stable in

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The results of this dose-finding study are in line with our

previous finding in a select group of hypercholesterolemic
men; that study showed that AGE supplementation can reduce platelet function (Steiner et al. 1996). The inhibitory
effect is selective, affecting collagen- and epinephrine-induced
aggregation more than that stimulated by ADP. To enhance
discriminatory activity of our sampling procedure, we analyzed
threshold concentration levels for each of the individual platelet agonists. In general, we found good reproducibility of
platelet responsiveness to a given stimulant over a period of
time. The exception to this rule was the intake of nonsteroidal
anti-inflammatory agents before blood collections for our experiments. This is a problem that becomes prevalent in a
long-term study. Therefore, we tested platelet aggregation with
arachidonic acid as a stimulant in each individual to detect
preceding use of nonsteroidal anti-inflammatory agents that
inhibit platelet aggregation.
It was interesting to note that the inhibitory effect of AGE
on platelet aggregation was not strictly dose dependent. At
least for epinephrine and ADP as stimulants, the lowest dosage
of AGE tested, i.e., 2.4 g extract/d, was as efficacious as the
higher dosages given. Only for collagen was there a progressive
increase at escalating dosage levels of AGE. But with this
agonist as well, the highest intake level of 7.2 g AGE/d did not
produce increased inhibition over and above that provided by
4.8 g AGE/d. Our studies showed clearly that the washout
period of 2 wk was sufficient to eliminate the antiaggregatory
activity of AGE.
Previous studies in humans and animals have shown that
certain constituents of fresh garlic or its extract have inhibitory activity on platelet aggregation (Ali and Mohammed
1986, Apitz-Castro et al. 1988 and 1994a, Ariga et al. 1981,
Bordia 1978, Boullin 1981, Lawson et al. 1992, Legnani et al.
1993, Makheja et al. 1980, Mohammad and Woodward 1986,
Srivastava 1984 and 1986, Vanderhoek et al. 1980). Although
most of the reported experiments used in vitro incubations
with garlic or its components, there were some ex vivo or in
vivo experiments as well (De Boer and Folts 1989, Legnani et
al. 1993) that showed an inhibitory effect at high concentrations of the test substance. There has been no consensus on
the possible mechanism of action, but because most of the
individual components of garlic tested were organosulfur compounds, a sulfhydryl groupmediated effect may be responsible.
Corroborating evidence has been provided in at least one
study using ajoene as the inhibitor (Apitz-Castro et al. 1994b).
AGE contains a number of organosulfur components (Weinberg et al. 1992), one of which, SAC, was used in our study to
monitor compliance of study participants and as documentation of the absorption of AGE from the intestinal tract. AGE
contains a large number of other substances, including carbohydrates, saponins and proteins; little is known concerning
their effect on platelet function, especially aggregation. For
this reason, it is premature to speculate on the mechanism of
action of AGE on platelet aggregation. However, the selectivity of platelet inhibition makes an effect of AGE on specific
receptors, e.g., that of epinephrine and collagen, a more likely
explanation for the AGE-induced reduction of platelet aggregation than an inhibition of mediators of platelet aggregation
such as those observed with nonsteroidal anti-inflammatory
agents.
This study represents the first detailed investigation of the
effect of AGE on platelet adhesion to a variety of adhesive
proteins. Our results showed a significant reduction of adhesion to collagen- and fibrinogen-coated surfaces. Dose escala-

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gastric and intestinal milieus, allicin was not absorbed (EgenSchwind et al. 1992). For this reason, we have the strong
conviction that not only is there a plausible basic rationale for
the efficacy of AGE, but we also have good evidence of its
effectiveness upon administration. The inhibition of individual risk factors important for the development of cardiovascular disease is not very great, but the inhibition of several risk
factors achieved by AGE should make it a very useful dietary
supplement in the prevention of cardiovascular disease.
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