Echinacea: a Miracle Herb against Aging and Cancer? Evidence In vivo in Mice

Abstract

Echinacea has been viewed as an immunoenhancing herb since it became commercially available several years ago. Indeed, its medicinal significance is responsible for billions of dollars in worldwide sales annually. Unfortunately, most of the 'evidence' for the purported medicinal efficacy of Echinacea has been anecdotal and, moreover, to this day, there is no formal proof on how to achieve the best results-whether it should be consumed daily throughout life as a prophylactic; consumed by either young or old; or consumed after diseases, such as cancer, have taken hold. Our work over the past 5 years has led to conclusive answers to some of these questions, at least in mice. Our results have shown that daily consumption of Echinacea is indeed prophylactic, extends the life span of aging mice, significantly abates leukemia and extends the life span of leukemic mice. Given that humans are 97% genetically common with mice and that virtually all our basic physiology is identical, it is neither unjustified to extrapolate these observations to humans nor would it be an arduous task to perform many of these studies in humans, thus establishing viable scientific evidence replacing the anecdotal.

Full text

eCAM 2005;2(3)309–314
doi:10.1093/ecam/neh118
Review
Echinacea: a Miracle Herb against Aging and Cancer?
Evidence In vivo in Mice
Sandra C. Miller
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
Echinacea has been viewed as an immunoenhancing herb since it became commercially available
several years ago. Indeed, its medicinal significance is responsible for billions of dollars in worldwide
sales annually. Unfortunately, most of the ‘evidence’ for the purported medicinal efficacy of Echinacea
has been anecdotal and, moreover, to this day, there is no formal proof on how to achieve the best
results—whether it should be consumed daily throughout life as a prophylactic; consumed by either
young or old; or consumed after diseases, such as cancer, have taken hold. Our work over the past 5 years
has led to conclusive answers to some of these questions, at least in mice. Our results have shown that
daily consumption of Echinacea is indeed prophylactic, extends the life span of aging mice, significantly
abates leukemia and extends the life span of leukemic mice. Given that humans are 97% genetically
common with mice and that virtually all our basic physiology is identical, it is neither unjustified to
extrapolate these observations to humans nor would it be an arduous task to perform many of these
studies in humans, thus establishing viable scientific evidence replacing the anecdotal.
Keywords: Echinacea – hemopoiesis – immunolo gy – leukemia – NK cells
Introduction
Natural Killer Cells and Echinacea: a Harmonious Duo
The herb, Echinacea, after making its debut on the world’s
commercial markets more than a decade ago, has become
one of the top-selling herbs of all time. Many of its ingredients
are powerful immune system stimulators. Its contents include
high molecular weight polysaccharides, essential oils, alkyl-
amides such as echinacein, isobutylamides such as penta-
decadienes and hexadecadienes, polyacetylene, tannins,
inulin, heteroxylan, flavonoids and vitamin C. Indeed, the bio-
chemistry and content definition of Echinacea and most other
herbs has taken place decades before the medicinal value of the
phytochemicals they contain ever merited investigation. Some
of the contents of Echinacea are natural killer (NK) cell stimu-
lants while others (the alkylamides) inhibit the endogenous
suppressors of NK cells, i.e. the prostaglandins. NK cells are
the first line of defense in cancer immunosurveillance, and
consequently any agent that will either stimulate these funda-
mental cel ls or remove any negative influence on them would
be clearly of medicinal value. In spite of the manifold func-
tions of the prostaglandins in vivo, it is clear that at least one
member of the prostaglandin family is detrimental to NK cells.
The alkamide family of compounds within Echinacea inhibits
the production of 5-lipoxygenase and cyclooxygenase, which
are enzymes needed for the production of prostaglandins
(1,2). Thus, reducing or eliminating this negative influence
should result in an absolute and functional increase in NK cells
(Fig. 1). Indeed, this is what we found some years ago when
the drug indomethacin, an inhibitor of these key enzymes in
prostaglandin formation, was administered in vivo to leukemic
mice. This drug in vivo resulted in statistically significant
increases in NK cell numbers and function in leukemic mice
(3,4). Unfortunately, indomethacin, as with most exogenously
administered drugs/factors, is beset with significant undesir-
able side effects that necessarily restrict its long-term use.
Furthermore, there is considerable evidence suggesting that
other phytochemicals in Echinacea might have the capacity
to reduce tumors and virus infections (5–10). Among the poly-
saccharides contained within Echinacea, the complex carbo-
hydrate group known as the arabinogalactans are particularly
For reprints and all correspondence: Sandra C. Miller, PhD, Department of
Anatomy and Cell Biology, McGill University, 3640 University Avenue,
Montreal, Quebec, Canada H3A 2B2. Tel: þ1-514-398-6358;
Fax: þ1-514-398-5047; E-mail: sandra.miller@mcgill.ca
Ó The Author (2005). Published by Oxford University Press. All rights reserved.
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significant (5,11,12). Macrophages upon stimulation by
arabinogalactans (Fig. 1) release, in turn, a host of NK cell
stimulants (11,13–16).
Consequently, any agent that contains these two valuable
compounds, both so beneficial to those cells acting at the first
line of defense, i.e. the NK cells, is worthy of investigation for
its prophylactic potential and its therapeutic value. It was
against this background, i.e. the medicinal potential of Echin-
acea in NK cell enhancement, that we undertook an in-depth
in vivo study of this herb in (i) aged mice and (ii) mice afflicted
with leukemia, under cont rolled laboratory conditions.
Virtually all that was known about the medicinal potential
of Echinacea had been established in vitro. Our first study, in
contrast, was conducted in vivo 5 years ago, and at that
time we investigated the effect on hemopoietic and immune
cells of daily dietary intake of this herb for 2 weeks (17). After
2 weeks, we analyzed quantitatively the absolute changes in all
the hemopoietic and immune cells in both the spleen and the
bone marrow, the latter being the organ of de novo generation
of all hemopoi etic and immune cells. The spleen, on the other
hand, is a major repository for all these cells since this organ is
on the blood circulatory highway. In the spleen there are cells
that reside and function therein, i.e. the cells mediating specific
(adaptive) immunity (T and B lymhocytes), as well as NK cells
and monocytes—both types being responsible for non-
specific, spontaneous and non-adaptive immunity. Other cells
involved in the disease defense process, i.e. the mature and
maturing cells of the granulocyte lineages (eosinophils, neut-
rophils and basophils) also either function in the spleen or
pass through it en route elsewhere.
In our analysis of the effect of Echinacea on the above-
mentioned cells, everything was standardized. The mice
were inbred and of identical age, weight and gender (male).
Moreover, housing conditions were identical between cages
of mice consuming Echinacea and those consuming untreated
diet. Th e quantity and quality of food and water were also
standardized among all cages—those receiving the herb in
the diet and those not given the herb (controls).
It is obviously of fundamental importance that Echinacea
itself, as with any agent given either prophylactically or thera-
peutically, is not deleterious to the host. In the case of
Echinacea, there appears to be no in vivo toxic level, i.e. over-
dose level, as defined by several assays and criteria (6,18,19).
The immu nostimulating effects of Echinacea in vivo are
exclusive to cells mediating spontaneous immunity and their
accessory cells, i.e. NK cells and monocytes (17). While
Echinacea appears to be tailor-made for its highly positive
influences on this arm of the immune system, there are
instances, in vivo, where use of this herb may be contraindic-
ated. For example, individuals demonstrating allergy to
members of the Family Asteraceae, to which Echinacea
belongs, would clearly be ill-advised to consume this
herb for any reason (20,21). Moreover , there is very little avail-
able information concerning the potential for detrimental
interactions of Echinacea with either other herbs or pharma-
ceuticals (22). Another problem pertains to the choice of the
most effective source of Echinacea as NK stimulant—not an
insignificant problem since there is extremely wide variation
in the quality of Echinaceas from assorted commercial
sources. For our experiments, we chose a product from a com-
mercial supplier, which we proved was consistent in quality
and NK stimulating potency, and revealed in dose–response
analyses, a progressive increment in NK cell numbers up to a
maximum (plateau) beyond which no further increase in NK
cells occurred. It was this dosage that we have used throughout
our experiments to date, including those reported in this
review.
Should Echinacea be Take n When Healthy?
When healthy young adult mice consumed Echinacea daily in
their diet for 7 days, we found significantly more NK cells,
identified by our standard immunoperoxidase labeling meth-
ods, in their bone marrow than in the bone marrow of mice
consuming untreated diet (P < 0.01), while the spleens of
mice consuming Echinacea had 25% more NK cells, which
is a clear elevation in number although not yet statistically sig-
nificant (17). By 2 weeks, however, those mice consuming the
Figure 1. Contained within Echinacea root extract is a family of complex
polysaccharides known as arabinogalactans. These sugars directly stimulate
macrophages to produce three cytokines that, in turn, directly stimulate NK
cells. The latter respond by means of new NK cell production/numbers and/
or increased lytic functional capacity. On the other hand, contained also within
Echinacea root extract are a group of molecules known as the alkamides, some
of which interact with two key enzymes essential to the production of prosta-
glandin E2 (PGE2). Normally, PGE2 is suppressive to NK cells. Consequently,
when the fundamental enzymes are blocked, PGE2 levels are negligible and
NK cells, now free of their suppressors, become increased in numbers and
function. Thus, via these two different avenues, i.e. stimulation indirectly
through macrophages, and release from suppressor factors (PGE2), whole
Echinacea is a powerful NK cell stimulant. The diagram of the Echinacea plant
is reproduced with permission from The Herbal Drugstore, LB White &
S Foster, Rodale Inc., 2000.
310 Echinacea against aging and cancer

herb had significantly more NK cells in their spleens and bone
marrow (P < 0.01). The early (7 days) elevation in absolut e
numbers of NK cells in the bone marrow necessarily indicated
that actual generation of new NK cells was underway in that
organ under the influence of Echinacea. The 25% increment
in the spleen simply reflected the increased new NK cel l pro-
duction, since it is well established that the spleen is major
site to which virtually all newborn, bone marrow-derived NK
cells unidirectionally migrate (via the blood). NK cells do
not recirculate back to the bone marrow (23–25). However,
during 2 weeks of daily Echinacea exposure, the elevating
levels of new NK cell production by the bone marrow resulted
in a supernormal export of these additional NK cells to the
spleen, such that there was indeed a statistically significant
increase in the numbers of NK cells in the spleen by 2 weeks
as well.
Also of considerable interest was the observation that the
‘helper’, or accessory, cells for NK cells, i.e. the monocytes,
were 25% more numerous in both the bone marrow and the
spleen of mice consuming the herb for 7 days, and were statist-
ically more numerous in both organs (P < 0.01) after 14 days
of the dietary herb (17). To our surprise, mature granu locytes
and their precursors, as well as all other lymphocytes (T and
B), and the red blood cell precursors remained steadfastly at
control levels (mice consuming untreated diet) in both the
spleen and the bone marrow, irrespective of whether mice
had consumed Echinacea for 7 days or 14 days. Moreover,
we have consistently shown in all our previous studies that
all mice on Echinacea-containing diets were clinically no dif-
ferent from littermates and cage mates consuming untreated
chow, with respect to body weight, coat texture and level of
activity. Our administration to mice of daily dietary doses of
this herb of 0.45 mg per 25 gm body weight was indeed
derived from the average recommended dose for adult humans
(averaged as 125 lb), indicated on the labels of Echinacea con-
tainers provided by several different suppliers.
Since our murine studies were carried out under highly con-
trolled conditions (above), with the only variable being the
presence or absence of dietary Echinacea, then the singularly
positive influence on NK cells and their accessory cells (mono-
cytes) must have resulted only from the presence of
Echinacea. A major observation of this finding is that
Echinacea appears able to influence new cell generation in
the NK/monocyte systems, as evid enced by the significant
bone marrow increments in these cell types. Thus, the elevated
numbers of these cells observed in the spleen is the direct result
of the increased cell proliferation in the bone marrow with sub-
sequent dissemination via the blood in the presence of
Echinacea.
Two corollaries may extend from this study. First, the fact
that these observations were made in normal, healthy adult
mice indicates that the presence of Echinacea in vivo may
have a prophylactic role, resulting in a sustained elevation
in the available supply of NK cells/monocytes—both
well-established and vitally important cell lineages in the
maintenance of spontaneous, non-adaptive defenses against
virus-mediated diseases and developing neoplasms. Second,
since Echinacea is able to stimulate new NK cell generation
in the bone marrow, could it also do so in aging and elderly
animals, where these cells are in progressive, age-mediated
decline and thus rejuvenate this potent disease (cancer)-
defense mechanism?
Can Echinacea be Growing in the Fountain of Youth?
It has been known for some years that NK (and T) cells decline
with age (26–31), and correspondingly, cancers of assorted
types increase with age in both mice and humans. Believing
that this inverse relationship between NK cell presence and
cancer was more than coincidental, we set out to investigate
some years ago, first, the mechanism whereby NK cells
decline with age, and secondly, to see if there was any way
that NK cells could be brought back to their levels in young
adulthood. We found (27) that the decline in NK cells with
age was the result of (i) reduced new NK cell production in
the bone marrow and (ii) reduced efficiency of the few mature
NK cells that were produced to bind to their target cells, hence
preventing subsequent killing of the offensive target. With
the success of our studies with Echinacea (above) in healthy,
young adult mice, we conducted the same sort of experiments
as in these mice, except we used healthy, elderly mice (32). We
demonstrated in these healthy, elderly mice, that it is not only
possible to increase the absolute numbers of NK cells in their
normal bone marrow generating site by feeding daily
(P < 0.004) Echinacea via the diet for 14 days but also to res-
urrect the functional capac ity (target cell binding/lysis) of
these new Echinacea-generated NK cells. Indeed, this herb in
the diet returned the numbers and function of NK cells in these
elderly animals to the levels of the young adult. In the spleens
of these Echinacea-consuming elderly mice, NK cell numbers
rose to levels 30% greater than those of their control cage
mates not consuming Echinacea. The lytic capacity
of this newly produced army of NK cells in these Echinacea-
consuming elderly mice (32) also returned to levels
equivalent to those of the young adult. These levels were
statistically significantly higher (P < 0.03–0.001) than the
killing capacity of identically treated elderly mice not consum-
ing Echinacea for 14 days.
These observations appear to apply uniquely to this herb
since we could never rejuvenate the NK cell-mediated com-
ponent of the immune system in elderly mice by any of the
other typical NK cell enhancers. For instance, we had previ-
ously found in such healthy, elderly mice that neither the
cytokines IL-2 nor the drugs indomethac in was able to stimu-
late NK cell numbers or function in aging mice (27), in spite
of the fact that both these agents are potent stimulators of
NK cell numbers and function in the young adult mouse. Fur-
thermore, in elderly humans, immunostimulating cytokines
such as the NK-stimulating IL-2 are significantly impaired
with respect to production levels and with respect to a
decreased ability of several types of immune cells from aged
humans to utilize IL-2 (31,33,34). Paralleling our observations
eCAM 2005;2(3) 311

with young adult mice consuming Echinacea for 14 days (17),
we did not find in these healthy elderly mice, any influence of
dietary Echinacea on the mature or precursor granulocytes, the
precursors to red blood cells or the other immune cells (T and
B lymphocytes) in either the spleen or bone marrow , again
indicating the unique role of Echinacea in stimulating the
non-adaptive limb of the immune response, i.e. NK cells and
their accessory cells, the monocyt es. Nevertheless, in spite of
our observations of these positive influences of Echinacea
consumption in aging mice, it must be borne in mind that sim-
ilar controlled experiments have not been, or can they really
ever be, conducted on human subjects simply because of the
variability among humans even of identical age and gender.
One reason for this, of course, is that precisely identical, life-
long life styles can never be achieved with the precision and
control readily achievable for laboratory animals.
Are the Parts as Good as the Whole?
In a subsequent study (35), we injected arabinogalactan
intraperitoneally daily for 7 days or 14 days into elderly
mice. Since this complex polysaccharide is contained in whole
Echinacea, it was hypothesized that this component might
have as good an effect on NK cells as did the extract of whole
herb. However, we found that in contrast to whole product, this
component was not effective in stimulating NK cell numbers
in the elderly mouse bone marrow or spleen. Arabinogalactan
was not effective in altering the levels of any other hemopoi-
etic or immune cell populations in either spleen or bone
marrow. However, when we injected arabinogalactan into
young adult mice the NK cell levels of the bone marrow
were decreased after 7 days and returned to control (sham-
injected) levels for that organ only after 14 days of daily
administration of the polysaccharide. In the spleen, ara-
binogalactan administration for 7 days produced no change
in the numbers of NK cells, and only after 14 days of daily
exposure to this agent did the leve ls of splenic NK cells rise
significantly (P < 0.004) above control levels. From these
findings, it appears that at least from a prophylactic standpoint,
it is more efficacious to administer whole Echinacea rather
than isolated compounds contained within the herb. As dis-
cussed above (see Introduction), in the case of Echinacea at
least, the whole product acts via two different mechanisms to
stimulate NK cells since the whole product contains both ara-
binogalactans and alkamides.
With respect to other herbs of known medicinal v alue, the
whole product may similarly contain many compounds that
may act additively or even synergistically to produce, collect-
ively, the best effects in vivo. The possibility that the collective
whole may be better than any single extracted compound,
is supported by already available circumstantial evidence
(15,36).
Is it Possible to Get Too Much of a Good Thing?
We elected next to study the influence of daily consumption of
Echinacea throughout life beginning in youth, i.e. 7 week of
age (puberty), until early ‘old age’ (13 months) in inbred
mice (37). There is considerable controversy concerning the
duration/frequency with respect to human consumption of
Echinacea. For example, the common label advice when pur-
chasing Echinacea over the counter indicates that Echinacea
should be taken for short spurts of time and then terminated
for several days/weeks before resuming intake. The untested
reasoning is that perhaps chronic overstimulation of the
immune system via daily, long-term exposure to Echinacea
could result in dependency, or worse, that immune system
activity may fall to very low levels, rendering it incompetent
to ward off even minor infections. Thus, in an effort to dispel
or prove this theory, we fed young mice, from 7 weeks of
age until 13 months, our standard, daily dose of Echinacea,
previously shown to be NK-enhancing, in the chow—all other
parameters strictly controlled (husbandry, gender, age, water/
food intake quant ity, etc.) as in our previous studies.
Our results (37), for the first time, provided concrete evid-
ence that chronic (long-term) intake of Echinacea was not
only not detrimental but also distinctly prophylactic. Mice in
control cages eating untreated chow had a 79% survival by
10 months of age, while mice living under identical conditions,
with the one variable being Echinacea in the daily chow, were
still 100% alive by 10 months of age. By 13 months of age,
control mice were 46% still alive, while those consuming
Echinacea were 74% alive. Furthermore, in the Echinacea-
consuming mice, NK cells were statistically significantly elev-
ated in absolute numbers at every sampling period, in both
their bone marrow generating site and their site of maximum
accumulation, the spleen (37). Given that the key immune cells
acting as the first line of defense against developing neoplasms
in mice and humans are NK cells, it is not difficult to conclude
that sustained enhancement of NK cells alone, throughout life,
could readily account for the reduced frequency in deaths with
advancing age. Sp ontaneous neopl asms, clinical ly undetect-
able, are well known to increase with advancing age in humans
and mice. Thus, the logical corollary from this study indicates
that chronic daily intake of Echinacea, is cle arly not detri-
mental to the immune system, but rather prophy lactic.
Will Echinacea ‘Work’ Once a Tumor is in Progress?
Since the debut of NK cells, leukemias and lymphomas have
been known to be targets for NK cytolysis. Indeed, NK cells
were, decades ago, established as the first line of defense
against these types of neoplasms (38–40). The concept that
herbal compounds can enhance NK cells has recently gained
considerable attention and indeed, excellent reviews on the
roles of NK cells in tumor combat and the role of such com-
pounds in modifying antitumor responses, have been provided
by Takeda and Okumura (41) and Cooper (42). Therefore, we
hypothesized that significantly enhancing NK cells, even after
leukemia has taken hold, may lead to actual elimination of
these tumor cell ‘targets’. Thu s, we induced leukemia in
mice via injection of a dose of leukemia cells known to con-
sistently result in death 3.5 weeks later, and on the same day
312 Echinacea against aging and cancer

as leukemia induction, Echinacea was added to their diet.
Control leukemia-injected mi ce consumed regular diet. All
other parameters of these experiments were identical, as usual
(above). The results were most encouraging (43). NK cell
numbers by 9 days after tumor onset were very significantly
elevated over control (P < 0.000007). Three months after
leukemia onset—long after all control (untreated chow) leuk-
emic mice had died—NK cells were recorded at more than
twice the numbers present in normal mice of identical age,
strain and gender. Furthermore, all the other hemopoietic and
immune cell lineages in both bone marrow and spleen in these
long-term, Echinacea-consuming, originally leukemic mice
were indistinguishable from the corresponding populations of
cells in normal mice. Life span analy sis indicated that not
only had Echinacea extended life span (43) but also the sur-
vival advantage provided to leukemic mice by consuming
Echinacea daily was statist ically significant (P < 0.022).
One-third of all Echinacea-consuming mice that survived
until 3 months after leukemia onset wen t on to live a full-
life. We believe that further manipulation of Echinacea dose/
frequency/duration regimens could allow many more if not
the othe r full two-thirds to go on to live a full life. The mech-
anism by which Echinacea mediates its antineoplastic activity
is well known (see Introduction). It acts exclusively via the
immune system and has no influence on the tumor cells them-
selves, the latter being highly unstable and continuously clon-
ing out their mos t virulent cells to produce frank neoplasm.
However, by stimulating the first line of defense, i.e. NK cells,
which are so effective in detecting and lysing tumor cells
immediately upon detection, the value of Echinacea can be
readily seen.
Thus, the medicinal value of phytochemicals contained in
Echinacea is clearly evident and indicates that these agents,
as well as phytochemicals not yet discovered in other herbs,
may be valuable tools to combat tumor. The therapeutic value
of Echin acea can now be added to its prophylactic potential
(above) and indicates that herbal therapy may soon see its
debut alongside—or indeed in place of—conventional therapy,
especially since virtually all chemo-‘therapy’ is so toxic to all
other renewing systems in the body, that its administration
(dose/frequency/duration) must necessarily be very limited,
and as such are not successful in achieving complete life-
long tumor eradication, i.e. cure.
Combination Therapy in Leukemia Combat—
Echinacea Helps Out Again
There is another powerful NK stimulant called melatonin,
which the mammalian body makes in the pineal gland,
and ‘its role is to act as a neuroimmunomodulator (44–48).
When we gave the combination of Echinacea and melatonin
(43), via the diet, daily to leukemic mice (leukemia induced
as above), not only did we find the usual significant elevation
in NK cells but also the long-term survival increased to 40%,
compared with the one-third of the leukemic mice when
Echinacea alone was given (above). Thus, at least for this
tumor, the two NK stimulants together were indeed better
than one.
In another type of combination therapy, we immunized mice
5 weeks beforehand, with killed leukemia cells (49) before
injecting live cells and daily dietary Echinacea. We observed
that the combination of immunization and dietary Echinacea
was substantially more therapeutic than either alone. Immun-
ization alone produced a survival rate and life span increment
similar to that achieved by giving leukemic mice dietary
Echinacea alone. Life span increment via combination therapy
has reached 60%. Moreover, when NK cells were measured at
3 months after leukemia injection (onset), it was found that the
absolute numbers of NK cells in their bone marrow birth site
was three times that of immunized mice not consuming Echin-
acea (P < 0.003), and the numbers of NK cells in the spleens
of immunized mice consuming daily dietary Echinacea rose to
almost twice (P < 0.001) the numbers found in immunized
mice not receiving the herb. In true ‘Echinacea style’, the
stimulatory effect of this herb was directed toward NK cells.
Consequently, by 3 months, the presence of this herb in the
diet of leukemic mice had no influence on the lymphocytes,
red blood cell precursors, mature granulocytes or their precurs-
ors in either spleen or bone marrow, again demonstrating the
uniquely positive influence of this herb on non-adaptive
immunity.
Therefore, it appears that combination therapy in which one
agent is Echinacea and the other, a non-toxic and non-
immunosuppressive agent (thus eliminating virtually all mod-
ern chemotherapeutic laboratory-derived concoctions) has
great advantage at least in leukemia treatment. Given that
humans and mice are 97% genetically common, with similar
physiology in virtually every organ, it is not unjustifiable to
extrapolate these collective findings to humans. Studies such
as these investigations with mice warrant assessment at the
clinical level especially since both Echinacea and melatonin,
and a host of other herbal products, are already in the market
place. Unless formal clinical studies follow, to establish regu-
latory guidelines, it is very conceivable that leukemia patients
(and others) could begin to self-medicate—with potentially
disasterous results (22).
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Received October 12, 2004; accepted July 29, 2005
314 Echinacea against aging and cancer