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Effects of the Dietary Flavonoid Quercetin Upon Performance and Health

Davis, J. Mark; Murphy, E. Angela; Carmichael, Martin D.

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Current Sports Medicine Reports: July-August 2009 - Volume 8 - Issue 4 - p 206-213
doi: 10.1249/JSR.0b013e3181ae8959
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Abstract

INTRODUCTION

The popularity of nonsynthesized, naturally occurring plant extracts and phytochemicals to enhance mental and physical performance, maintain health, and prevent disease has increased dramatically in recent years due in part to the fact that they are accessed more easily, generally are less expensive, and are thought to have fewer side effects than manufactured drugs. The use of herbs and botanicals for these purposes has occurred for millennia, but not until recently have these substances been subjected to systematic experimental validation. One important plant-derived substance that has shown great promise is quercetin. Quercetin (3,4,5,7-pentahydroxylflavone) is a typical flavonoid, the most well defined group of polyphenolic compounds, and is abundant in many commonly consumed fruits and vegetables, particularly apples, cranberries, blueberries, and onions (24). Its physical properties are derived from its hydrophobic, co-planar structure, while its chemical properties arise from the electron donating activity (reducing activity) of its phenolic hydroxyl group (24). However, substantial pre-clinical data show that quercetin has numerous biological effects beyond its antioxidant activity, including antiinflammatory, anticarcinogenic, antiviral, psychostimulant, cardioprotective, and neuroprotective properties (1,14,24,55). Of particular interest is recent evidence in mice that quercetin can increase mitochondrial biogenesis (13), which could have profound consequences upon both performance and health if it can be translated clinically (Fig. 1).

FIGURE 1
FIGURE 1:
The multiple biological properties of the dietary flavonoid quercetin have been associated with performance and health benefits.

Because the beneficial effects of a supplement like quercetin are largely dependent on its bioavailability after oral administration, the absorption, distribution, metabolism, and excretion of quercetin have been studied extensively in both laboratory animals and humans. Although initial reports indicated that bioavailability of quercetin was limited, recent evidence suggests otherwise. Our pharmacokinetic data on doses of pure quercetin being used in clinical trials show that quercetin can be detected in plasma within 15-30 min of ingestion of a 250 or 500 mg quercetin chew preparation, reaching a peak concentration at approximately 120-180 min, returning to baseline levels at 24 h in humans (Fig. 2). Our results are consistent with those of others that have measured quercetin absorption and appearance in the plasma after ingestion of the pure quercetin aglycone as well as various gluconated forms contained in foods such as shallots, onions, and apples (22). Quercetin also has been shown to reach and accumulate in various tissues including colon, kidney, liver, lung, muscle, and brain (16), although the tissue distribution has not yet been studied in humans. Quercetin has GRAS status (generally recognized as safe) according to criteria established by the U.S. Food and Drug Administration (FDA) (24,55). There are no reports of harmful side effects in animals or humans at doses of several grams per day. This article will briefly examine the available literature concerning quercetin's potential role in mental and physical performance, health, and disease. It is not intended to be a comprehensive review because of space limitations and is weighted more heavily on an overview of the wealth of preclinical data because human studies are just beginning to appear in the literature.

FIGURE 2
FIGURE 2:
Total plasma quercetin concentration following oral administration of 250 mg (low dose) and 500 mg (high dose) of quercetin (QU-995). * Significantly different than low dose (P < 0.05). Study Design: 10 subjects participated in a randomized crossover study following 3 d of a quercetin-free diet. Subjects received each dose 1 wk apart. After a 3-h fast, 7 mL of blood were collected before and 15, 30, 60, 90, 120, 180, 360, and 1440 min following quercetin ingestion in the form of a soft chew (manufactured by Nutravail, Chantilly, VA). Analytical Procedures (modified from Neiman et al., 2007): Plasma samples underwent enzymatic hydrolysis followed by solid phase extraction with methanol elution. Samples were then concentrated, and 50 uL injections were analyzed via HPLC-UV at 370 nm. Mobile phase consisted of MeOH and dH2O (80:20, v/v) with flow rate of 0.5 mL·min−1. Quantification of quercetin peak was based upon the standard addition method with blank plasma as matrix.

PERFORMANCE

There is good evidence to support the hypothesis that quercetin may be able to increase endurance exercise capacity. The evidence comes primarily from in vitro and in vivo studies in rodents that show that quercetin has a combination of biological properties known to affect both physical and mental performance, including antioxidant (24), and anti-inflammatory activity (24), psychostimulant effects (1), and perhaps most exciting, the ability to increase mitochondrial biogenesis in both the muscle and brain of mice (13).

Quercetin's powerful antioxidant activity may contribute to its beneficial effect upon exercise performance. The radical scavenging activity of quercetin is largely a function of the chemical structure of quercetin, particularly the presence of the hydroxyl (−OH) substitutions and the catechol-type B-ring (24). Although the generation of some reactive oxygen species (ROS) is likely necessary for normal muscular adaptation, very large and/or prolonged increases may be counterproductive and can cause fatigue in rodents (47). The relationship between ROS production and endurance performance in humans is less clear (36,47).

With respect to antiinflammatory properties, quercetin has been shown to modulate intracellular signaling pathways, including the inflammatory signaling cascade, by inhibiting activation of the important proinflammatory transcription factor nuclear factor-kappaB (NF-κB) among others (24). Strenuous exercise that is novel or predominately eccentric in nature is capable of damaging muscle and initiating an inflammatory response. Cell culture studies and in vivo animal studies provide good evidence for an anti-inflammatory effect of quercetin (24); however, evidence from human trials is less clear. For example, Nieman et al. examined the effect of quercetin upon inflammation after three consecutive days of cycling and following an ultra-long endurance run. Except for an attenuation of IL-8 and IL-10 mRNA in blood leukocytes following the cycling bouts, quercetin failed to attenuate any of the measured markers of muscle damage, inflammation, increases in plasma cytokines, and alterations in muscle cytokine mRNA expression (39,40).

Another interesting property of quercetin that may enhance mental and physical performance is its caffeine-like psychostimulant effect. Numerous studies have shown that psychostimulants like caffeine can delay fatigue during endurance exercise, at least in part because of their ability to block adenosine receptors in the brain, which results in large part in an increase in dopamine activity (15). Various flavonoids also possess adenosine A1 receptor antagonist activity in vitro (1). Of the flavonoids that were tested, quercetin was shown to have the highest affinity for this receptor, which was similar to caffeine (1). Further evidence for this effect in mice comes from our laboratory that shows increased gene expression of adenosine A1 receptors in the brain following 7 d of quercetin feedings. In contrast, a recent study in humans designed to compare the psychostimulant effects of quercetin and caffeine reported no effect of a large single dose of quercetin (2 g) upon exercise performance in the heat (7). However, it is not certain to what extent the thermal stress may have diminished the possible benefits of quercetin because the typical ergogenic benefit of caffeine also was not detected under these conditions.

Perhaps the most important novel effect of quercetin related to a possible benefit on endurance performance comes from recent in vitro and rodent studies that show a benefit on mitochondrial function. In vitro evidence exists for an effect of quercetin on mitochondrial biogenesis (46). Further, evidence is accumulating to show that natural flavonoids, such as quercetin and resveratrol, and flavonoid derivatives (i.e., drugs), can increase mitochondrial biogenesis via intracellular signaling pathways involving peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and sirtuin 1 (SIRT1), which have been linked to improved endurance and health in mice (33,46). We found that quercetin feedings (12.5 and 25 mg·kg−1·d−1) for 7 d increased markers of mitochondrial biogenesis, including PGC-1α and SIRT1 gene expression (Fig. 3A-D), mitochondrial DNA (mtDNA) (Fig. 3E-F), and cytochrome c enzyme concentration in both brain and soleus muscle (13).

FIGURE 3
FIGURE 3:
Short-term feedings of the dietary flavonoid quercetin increase expression of genes associated with mitochondrial biogenesis, mtDNA number, and both voluntary and involuntary endurance performance. PGC-1α and SIRT1 expression (A-D) and mtDNA (E-F) were increased in skeletal muscle and brain after 7 d of quercetin feedings (N = 15 in each group). After 7 d of quercetin feedings, mice were run to fatigue on a treadmill, and run time was recorded (N = 16 in each group). Both doses of quercetin increased run time to fatigue (G). For voluntary activity, mice were fed quercetin (25 mg·kg−1) or placebo in the form of a palatable rodent pellet daily for 7 d (N = 18 in each group). Voluntary activity was monitored throughout the 7 d of quercetin feedings and for 7 d post-quercetin feedings. Distance run, time on the wheel, and peak speed were analyzed (H-J). Quercetin increased distance on days 6-14 (P < 0.05), time on the wheel on days 7 and 14 (P < 0.05), and peak speed on days 2 and 3 (P < 0.05). Values are means ± SEM. *Significantly different from placebo (P < 0.05). [Adapted from Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial bigenesis and exercise tolerance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296:R1071-7. Copyright © 2009 American Physiological Society. Used with permission.]

Direct evidence for a benefit of quercetin upon endurance performance is limited. Davis et al. showed in mice that short-term quercetin feedings increased both maximal endurance capacity and voluntary physical activity (13). Quercetin feedings at a dose of 12.5 and 25 mg·kg−1·d−1 for 7 d increased treadmill run time to fatigue at approximately 70% V˙O2max by 36% and 37%, respectively (Fig. 3G). Quercetin at the higher dose (only dose tested) also increased voluntary wheel-running activity (Fig. 3H-J). These performance benefits were associated with increased mitochondrial biogenesis in both brain and muscle that are likely to explain, at least in part, the physical and mental factors responsible for these beneficial effects.

To evaluate these findings clinically, we recently examined the effects of 7 d of quercetin (500 mg twice daily, a dose similar to the 12.5 mg·kg−1 dose that was administered in the mouse study) implementation on both V˙O2max and time to fatigue on a bicycle ergometer in healthy untrained men and women. An increase in both V˙O2max (3.9%) and ride time to fatigue (13.2%) were found (12). The underlying mechanisms were not investigated in this study. A limited number of other studies also have investigated the effects of quercetin on endurance performance in humans with mixed results. MacRae et al. (34) reported that a commercial beverage containing quercetin (FRS, The FRS® Company, Foster City, CA) was able to improve bike time trial performance slightly in highly trained cyclists when ingested at a dose of 600 mg·d−1 (2 × 300 mg twice daily) for a period of 6 wk (34). However, the specific effects of quercetin in this study could not be determined because quercetin was administered in combination with caffeine and tea catechins that may have interacted positively or negatively with quercetin. Quindry et al. reported that quercetin supplementation (250 mg × four times daily for 3 wk) had no effect upon race performance at the Western States 100-mile race (44). However, this study was not designed to measure performance but rather to look at quercetin as a countermeasure for immune perturbations and upper respiratory tract infections that are known to occur following stressful exercise. A single very high dose of quercetin (2 g) also was shown recently not to increase exercise performance in moderately fit military personnel during exercise in the heat (7). However, in this study caffeine administration at a dose that typically increases endurance performance also was not effective.

The available evidence for a beneficial effect of quercetin upon endurance performance, while very promising, is limited by the dearth of sophisticated clinical trials. The available clinical trials are limited by a lack of fundamentally important information necessary to design studies that will allow strong conclusions about the role of dietary quercetin upon endurance performance. Studies with negative findings are of particular concern at this early stage of investigation given the multitude of as yet unknown factors that could affect the outcome of the study, including optimal timing, dose, and delivery of quercetin, individual differences in bioavailability, subject's fitness and training status, environmental influences, and mode and intensity of exercise, to name a few.

INFECTION

Good evidence is available to show that exercise stress can decrease immune function and increase the risk for upper respiratory tract infection (URTI) in both animals (14) and humans (38). Various nutritional strategies have been examined as possible countermeasures for these responses during periods of intense training and competition with little successes (38). Data from cell culture experiments provide strong evidence that quercetin may be effective in this regard. Quercetin has been reported to reduce infectivity of target cells and subsequent replication against a wide variety of respiratory viruses, including herpes simplex viruses (HSV-1 and HSV-2) (17), adenoviruses (ADV-3, ADV-8, ADV-11) (8), parainfluenza virus type 3 (Pf-3), respiratory syncytial virus (RSV) (28), and severe acute respiratory syndrome (SARS) (6) in cell culture studies. The precise mechanisms of this effect are not known. However, it has been shown that quercetin can block viral replication at an early stage of multiplication for several respiratory viruses by inhibition of proteases by molecular docking, suppression of virulence enzymes such as DNA gyrase and cellular lipase, and by binding of viral capsid proteins (6,8,11). It also is possible that quercetin's antiviral activity effects may be mediated through induction of interferon; quercetin induces the gene expression and production of helper T lymphocyte-1 (Th-1)-derived interferon gamma (IFNγ), and it downregulates Th-2 derived interleukin 4 (IL-4) when cultured with human peripheral blood mononuclear cells (PBMC) (37). Quercetin also may enhance the activity of a variety of immune system components. Data from in vitro and animal studies have reported that flavonoids like quercetin can increase natural killer cell lytic activity, neutrophil chemotaxis, and mitogen-stimulated lymphocyte proliferation (2,37).

As with the possible benefits of quercetin on endurance performance, the in vivo data in animals and humans on susceptibility to infection is limited. Davis et al. used an established mouse model of exercise and respiratory infection to determine whether quercetin feedings (12.5 mg·kg−1 for 7 d prior to infection) could provide protection from respiratory influenza virus infection at rest and after 3 d of exhaustive exercise (14). Data indicate that quercetin feedings offset the exercise stress induced increase in morbidity (time to sickness), symptom severity, and mortality (time to death) in mice after intranasal inoculation with a standardized dose of influenza virus (A/Puerto Rico/8/34 (H1N1)). A strong trend toward a decrease in susceptibility to infection also was found in rested non-stressed mice following quercetin treatment.

Nieman and colleagues also have studied these effects in human subjects. In one study, quercetin feedings reduced self-reported symptoms of upper respiratory tract infection following 3 d of exhaustive exercise (41). In this study, highly trained cyclists ingesting 1000 mg·d−1 of quercetin over a 3-wk period experienced a significantly lower incidence of upper respiratory infection during the 2-wk period following the 3 d of intensified training. However, there were no beneficial effects of quercetin on any of the immune components measured, including natural killer cell lytic activity, polymorphonuclear respiratory burst, or PHA-stimulated lymphocyte proliferation despite the reduced incidence of URTI symptoms that were observed after quercetin feedings (41). However, in a similar study, Henson et al.reported no benefits on illness rates following the Western States Endurance Run (25). No effects of quercetin were found on leukocyte subset counts, granulocyte respiratory burst activity, and salivary IgA following quercetin supplementation for 3 wk before and 2 wk after the Western States Endurance Run (25). However, it's important to note that many immune system parameters that have been shown to play critical roles in susceptibility to respiratory infection could not be measured in these human studies. While good evidence exists for quercetin's antiviral effects in cell culture and animal studies, evidence in humans is lacking. Just as in the case of the ergogenic benefit of quercetin, it is too soon to make strong conclusions regarding the role of quercetin in infectious illness. More research is needed on type of pathogen, dose, and timing of quercetin administration, the mode, duration and intensity of exercise, and the timing of virus administration in relation to quercetin treatment.

CHRONIC DISEASE

The fact that quercetin appears to mimic some of the effects of exercise training and regular physical activity suggests that it also may benefit various chronic diseases, such as diabetes, neurodegeneration, cardiovascular disease, and cancer, in which inactivity, mitochondrial dysfunction, and/or oxidative stress/inflammation are hallmarks. However, as is the case for other aspects of quercetin's effects on performance and health, the evidence in this area also is limited by a lack of clinical trials.

Diabetes

Diabetes mellitus is one of the most common metabolic disorders. Given the consensus that is developing that mitochondrial dysfunction, inflammation, and reactive oxygen species play an important role in the development of insulin resistance and diabetes, it would seem reasonable that quercetin also may be helpful in the prevention and treatment of diabetes. In one study, quercetin administered in doses of 10-50 mg·kg−1 normalized blood glucose levels, augmented liver glycogen content, and significantly reduced serum cholesterol and LDL concentration in alloxan diabetic rats (42). Quercetin also was effective in reducing insulin resistance, hyperlipidemia, and inflammation in fatty Zucker rats (48). However, Stewart et al. recently found that a relatively high dose of quercetin (0.8% in the diet) did not alter the temporal progression of insulin resistance in diet-induced obesity in mice (54). Nevertheless, the authors did suggest that their negative findings clearly could be caused by the high dose of quercetin used, especially given the beneficial effects of significantly lower doses of quercetin in genetic models of insulin resistance (48). Several human epidemiological studies have examined the relationship between flavonoid intake and diabetes. A prospective cohort study by Knekt et al. reported that individuals who were identified as having higher quercetin intakes in the study population had a lower risk of type 2 diabetes (32). In contrast, a large prospective study of U.S. middle-aged and older women, reported no association between risk of type 2 diabetes and the intake of total and individual flavonols and flavones or flavonoid rich foods (52). However, women who ate one apple daily had an approximately 30% lower risk of developing type 2 diabetes than those who consumed no apples (52). These studies are however limited in their ability to detect a specific effect of quercetin upon risk of diabetes by a multitude of factors including measurement error in assessing flavonoid intakes and distinguishing effects of quercetin versus other flavonoids. Long-term intervention trials clearly are needed to substantiate the claims from in vitro and animal studies for a beneficial effect of quercetin on diabetes.

Neurodegeneration

Neurodegeneration describes the progressive loss of neuronal function and is exhibited in several predominant diseases including Alzheimer's disease (AD), Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), epilepsy, and stroke. While little is known regarding the precise causes of neurodegenerative diseases, aging clearly has been identified as an important risk factor. Oxidative damage, inflammation, and mitochondrial dysfunction have a well-known role in the aging process and are thought at least partly to mediate the development of neurodegenerative diseases, and it is in this regard that quercetin may convey its benefits.

Quercetin has been shown to have a neuroprotective effect against oxidative damage in several in vitro studies (56). It can protect nerve cells from oxidative damage (26) while promoting their differentiation (49) and has been shown to be effective at reducing lipid peroxidation produced by certain drug treatments (19). Quercetin's effects on oxidative stress may prove especially promising in developing strategies for the treatment of AD as it has been shown to have protective effects against Abeta (1-42) toxicity by modulating oxidative stress (4). Further, quercetin can inhibit the fibril formation of Aβ protein through its antioxidant properties (31).

The apparent beneficial effect of quercetin upon brain mitochondrial biogenesis (13) also could provide the basis for prevention and/or treatment of various neurodegenerative diseases. Impaired mitochondrial function has been linked closely to neurodegenerative diseases because of their important role in metabolism, oxidative stress, Ca2+ homeostasis, and cell death. Individuals suffering from AD, for instance, have reduced brain energy metabolism and decreased cytochrome C oxidase, an essential mitochondrial enzyme. Other investigators have shown that modulation of the transcriptional coactivators sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) that are primary regulators of mitochondrial biogenesis can extend lifespan (10). It is interesting to note that Aβ protein recently has been shown to have profound negative effects upon mitochondrial function (20).

Quercetin's powerful antiinflammatory activity also may be helpful in most neurological diseases that are now known to be associated with chronic inflammation within the brain. Quercetin can modulate enzymes and transcription factors within pathways essential in inflammatory signaling, including those which are involved in the IL-1β signaling cascade (24). For example, quercetin was shown to reduce the expression of proinflammatory cytokines and other inflammatory mediators such as COX-2 and NF-κB in many cell types including astrocytes following treatment with inflammatory agents and conferred protection against IL-1beta-induced astrocyte-mediated neuronal damage (50).

This evidence supports the hypothesis that quercetin may be helpful in the prevention and treatment of neurodegenerative diseases. However, there are no human epidemiological or experimental studies to report. There is evidence that consumption of foods rich in polyphenols like quercetin is associated with reduced risk of neurodegenerative diseases (56).

Cardiovascular Disease

Heart diseases are the leading cause of mortality in developed countries. The precise mechanisms involved in their development remain undiscovered but oxidative stress and inflammation play a necessary role. Quercetin is being investigated widely for its potential use as a safe alternative to antioxidant and anti-inflammatory drugs in a variety of conditions, including cardiovascular disease (32). Both preclinical and clinical data suggest that quercetin can reduce several of the risk factors associated with heart disease, including blood pressure (21) and cytokine-induced C-reactive protein (CRP) expression (29). It has been shown to possess cardioprotective affects across several models including ischemia/reperfusion-injury and H2O2-induced oxidative stress models (3), and it has been identified as having potent vasodilatory effects in coronary and resistance vessels (9).

Abundant epidemiological evidence suggests that people consuming diets high in flavonoid content are less likely to suffer from heart disease. In a prospective cohort study by Knekt et al. individuals who were identified as having higher quercetin intakes in the study population had lower mortality from ischemic heart disease. Relatively moderate amounts of quercetin (equivalent to that found in two glasses of red wine) have been shown to possess clot "busting" activity by rapidly increasing tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) mRNA expression in thoracic aortic endothelium (5); two important components of the endothelial cell fibrinolytic system. It is evident that flavonoids are potent bioactive molecules; however, quercetin's effectiveness as a cardioprotectant still needs to be evaluated in phase III clinical trials. Furthermore, a clear understanding of the mechanisms of action of quercetin is crucial to the evaluation of its potential role in heart disease.

Cancer

Among the diverse range of biological properties exhibited by quercetin include anticarcinogenic properties. The effects of quercetin on cancer have been tested largely in cell culture models, where it has been shown that quercetin can inhibit carcinogenesis via antimutagenic activity, antioxidant activity, antiinflammatory mechanisms, modulation of signal transduction pathways, and apoptosis-inducing and anti-proliferative activity. Quercetin's antimutagenic activity has been shown against aflatoxin B1 (AFB1) and 2-acetamido-flurene (2-AAF)-induced mutagenesis (51). Quercetin is one of the most potent antioxidant polyphenols, which is likely to reduce increased ROS produced in cancer cells that has been linked to genomic instability and cancer initiation, progression, and maintenance (24). The well-described anti-inflammatory effects of quercetin also are important because inflammation clearly is involved in various steps in tumorigenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis. Two key mechanisms of quercetin's antiinflammatory effect are its inhibition of NF-κB and COX-2 activity, which has been shown to occur in a human carcinoma cell line (HCT 116) (27) and human adenocarcinoma cells (Caco2) (43), respectively. There have been numerous reports on the effects of quercetin on signal transduction pathways associated with the process of carcinogenesis, including cell cycle regulation, apoptosis, and angiogenesis. For example, quercetin can induce apoptotic cell death through the mitochondrial pathway (23) and downregulate the expression of various oncogenes (45).

While good in vitro evidence supports a beneficial role of quercetin in cancer, in vivo animal studies of carcinogenesis have yielded inconsistent results, and there are no experimental studies in humans. For example, whereas Deschner et al. reported that a 2% quercetin diet inhibited azoxymethane-induced hyperproliferation in mice and reduced tumor incidence by 76% and tumor multiplicity by 48% (18), no beneficial effects were observed in the ApcMin/+ mice model of colon cancer treated with the same dose of quercetin (35). However, preliminary evidence in our laboratory has shown that a 0.02% quercetin diet can reduce intestinal tumorgenesis in ApcMin/+ mice and reduce tumor number in the C3 (1) SV40 Tag mouse model of breast cancer (Davis, JM, unpublished observations). In another study, quercetin had no effect upon skin tumorgenesis (53), but it did inhibit N-nitrosodiethylamine-induced lung tumorigenesis (30). The inconsistencies in the literature are probably caused by the differences in the cancer model, dose of quercetin, and timing of administration in relation to stage of cancer. The available human epidemiology data also are mixed, with some showing an inverse association between quercetin intake and cancer (32), while others do not.

CONCLUSION

The dietary flavonoid quercetin is emerging as a possible safe and effective nutritional supplement to enhance exercise performance, maintain health, and reduce chronic disease. The unique interrelated biological properties of quercetin, including its potent antioxidant and antiinflammatory activity, as well as the ability to increase mitochondrial biogenesis, make it a very exciting target for further study. One of the important distinctions between quercetin and the many other plant-derived polyphenols like resveratrol (33) that are being studied in this context is its availability at relatively low cost for use in clinical trials.

Quercetin has been shown to increase both maximal endurance capacity and voluntary physical activity in mice, an effect that is associated with increased mitochondrial biogenesis in brain and muscle (13). A similar effect in human subjects has been shown in some, but not in all studies. Quercetin also has been shown to reduce susceptibility to influenza infection following stressful exercise in a controlled experimental virus challenge model in mice (14). This also was confirmed in terms of URTI in humans in one study but not another (25,41). This has obvious potential ramifications for athletes and military personnel. There also is good evidence to support a benefit of quercetin on various chronic diseases like cardiovascular, metabolic (e.g., type 2 diabetes) and neurodegenerative diseases, and cancer. However, in all these cases, the preponderance of evidence comes from preclinical studies. The few clinical studies are inconsistent and inconclusive, which is not uncommon in the early stages of any investigation of a novel nutritional supplement in humans. At minimum, the findings provide a compelling argument for further research, especially well-designed clinical trials, to determine the specific role of quercetin in health and performance with a clear understanding of the mechanisms of action. If future research continues to support the hypothesized benefits of quercetin on health and performance, it could turn out to be an extremely important new discovery in nutrition.

Acknowledgment

This work was supported by grants from the Department of Defense Combat Feeding Program (W911QY-07-C-0033) and the Defense Advanced Research Projects Agency (DARPA) (W911NF-07-1-0140).

References

1. Alexander SP. Flavonoids as antagonists at A1 adenosine receptors. Phytother. Res. 2006; 20:1009-12.
2. Alvarez P, Alvarado C, Puerto M, et al. Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals. Nutrition. 2006; 22:913-21.
3. Angeloni C, Spencer JP, Leoncini E, et al. Role of quercetin and its in vivo metabolites in protecting H9c2 cells against oxidative stress. Biochimie. 2007; 89:73-82.
4. Ansari MA, Abdul HM, Joshi G, et al. Protective effect of quercetin in primary neurons against Abeta(1-42): relevance to Alzheimer's disease. J. Nutr. Biochem. 2008.
5. Booyse FM, Pan W, Grenett HE, et al. Mechanism by which alcohol and wine polyphenols affect coronary heart disease risk. Ann. Epidemiol. 2007; 17:S24-31.
6. Chen L, Li J, Luo C, et al. Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features. Bioorganic Medicinal Chemistry. 2006; 14:8295-306.
7. Cheuvront SN, Ely BR, Kenefick RW, et al. No effect of nutritional adenosine receptor antagonists on exercise performance in the heat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296:R394-401.
8. Chiang LC, Chiang W, Liu MC, Lin CC. In vitro antiviral activities of Caesalpinia pulcherrima and its related flavonoids. J. Antimicrob. Chemother. 2003; 52:194-8.
9. Cogolludo A, Frazziano G, Briones AM, et al. The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation. Cardiovasc. Res. 2007; 73:424-31.
10. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004; 305:390-2.
11. Cushnie TP, Lamb AJ. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents. 2005; 26:343-56.
12. Davis JM CC, Chen S, Carmichael MD, Murphy EA. The dietary flavonoid quercetin increases VO2max and endurance capacity. Int. J. Sport Nutr. Exerc. Metab. 2009 (in press).
13. Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296:R1071-7.
14. Davis JM, Murphy EA, McClellan JL, et al. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008; 295:R505-9.
15. Davis JM, Zhao Z, Stock HS, et al. Central nervous system effects of caffeine and adenosine on fatigue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 284:R399-404.
16. De Boer VC, Dihal AA, van der Woude H, et al. Tissue distribution of quercetin in rats and pigs. J. Nutr. 2005; 135:1718-25.
17. Debiaggi M, Tateo F, Pagani L, et al. Effects of propolis flavonoids on virus infectivity and replication. Microbiologica. 1990; 13:207-13.
18. Deschner EE, Ruperto J, Wong G, Newmark HL. Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis. 1991; 12:1193-6.
19. Dietrich-Muszalska A, Olas B. Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro. World J. Biol. Psychiatry. 2009; Feb 19:1-6 [Epub ahead of print].
20. Eckert A, Hauptmann S, Scherping I, et al. Oligomeric and fibrillar species of beta-amyloid (Abeta42) both impair mitochondrial function in P301L tau transgenic mice. J. Mol. Med. 2008; 86:1255-67.
21. Edwards RL, Lyon T, Litwin SE, et al. Quercetin reduces blood pressure in hypertensive subjects. J. Nutr. 2007; 137:2405-11.
22. Egert S, Wolffram S, Bosy-Westphal A, et al. Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J. Nutr. 2008; 138:1615-21.
23. Granado-Serrano AB, Martin MA, Bravo L, et al. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr. 2006; 136:2715-21.
24. Harwood M, Danielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem. Toxicol. 2007; 45:2179-205.
25. Henson D, Nieman D, Davis JM, et al. Post-160-km race illness rates and decreases in granulocyte respiratory burst and salivary IgA output are not countered by quercetin ingestion. Int. J. Sports Med. 2008; 29:856-63.
26. Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J. Agric. Food Chem. 2004; 52:7514-7.
27. Katula KS, McCain JA, Radewicz AT. Relative ability of dietary compounds to modulate nuclear factor-kappaB activity as assessed in a cell-based reporter system. J. Med. Food. 2005; 8:269-74.
28. Kaul TN, Middleton E, Ogra PL. Antiviral effect of flavonoids on human viruses. J. Med. Virol. 1985; 15:71-9.
29. Kaur G, Rao LV, Agrawal A, Pendurthi UR. Effect of wine phenolics on cytokine-induced C-reactive protein expression. J. Thromb. Haemost. 2007; 5:1309-17.
30. Khanduja KL, Gandhi RK, Pathania V, Syal N. Prevention of N-nitrosodiethylamine-induced lung tumorigenesis by ellagic acid and quercetin in mice. Food Chem. Toxicol. 1999; 37:313-8.
31. Kim H, Park BS, Lee KG, et al. Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J. Agric. Food Chem. 2005; 53:8537-41.
32. Knekt P, Kumpulainen J, Jarvinen R, et al. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 2002; 76:560-8.
33. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006; 127:1109-22.
34. MacRae HS, Mefferd KM. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int. J. Sport Nutr. Exerc. Metab. 2006; 16:405-19.
35. Mahmoud NN, Carothers AM, Grunberger D, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis. 2000; 21:921-7.
36. McAnulty SR, McAnulty LS, Nieman DC, et al. Chronic quercetin ingestion and exercise-induced oxidative damage and inflammation. Appl. Physiol. Nutr. Metab. 2008; 33:254-62.
37. Nair MP, Kandaswami C, Mahajan S, et al. The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochimica Biophysica Acta. 2002; 1593:29-36.
38. Nieman DC. Immunonutrition support for athletes. Nutr. Rev. 2008; 66:310-20.
39. Nieman DC, Henson DA, Davis JM, et al. Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA. J. Appl. Physiol. 2007; 103:1728-35.
40. Nieman DC, Henson DA, Davis JM, et al. Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run. J. Interferon Cytokine Res. 2007; 27:1003-1011.
41. Nieman DC, Henson DA, Gross SJ, et al. Quercetin reduces illness but not immune perturbations after intensive exercise. Med. Sci. Sports Exerc. 2007; 39:1561-9.
42. Nuraliev Iu N, Avezov GA. [The efficacy of quercetin in alloxan diabetes]. Eksp. Klin. Farmakol. 1992; 55:42-4.
43. O'Leary KA, de Pascual-Tereasa S, Needs PW, et al. Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutation Res. 2004; 551:245-54.
44. Quindry JC, McAnulty SR, Hudson MB, et al. Oral quercetin supplementation and blood oxidative capacity in response to ultramarathon competition. Int. J. Sport Nutr. Exerc. Metab. 2008; 18:601-16.
45. Ranelletti FO, Maggiano N, Serra FG, et al. Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int. J. Cancer. 2000; 85:438-45.
46. Rasbach K, Schnellmann RG. Isoflavones promote mitochondrial biogenesis. J. Pharmacol. Exp. Ther. 2008; 325:536-43.
47. Reid MB. Free radicals and muscle fatigue: of ROS, canaries, and the IOC. Free Radic. Biol. Med. 2008; 44:169-79.
48. Rivera L, Moron R, Sanchez M, et al. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity. 2008; 16:2081-7.
49. Sagara Y, Vanhnasy J, Maher P. Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation. J. Neurochem. 2004; 90:1144-55.
50. Sharma V, Mishra M, Ghosh S, et al. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res. Bull. 2007; 73:55-63.
51. Snijman PW, Swanevelder S, Joubert E, et al. The antimutagenic activity of the major flavonoids of rooibos (Aspalathus linearis): some dose-response effects on mutagen activation-flavonoid interactions. Mutat. Res. 2007; 631:111-23.
52. Song Y, Manson JE, Buring JE, et al. Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. J. Am. Coll. Nutr. 2005; 24:376-84.
53. Steerenberg PA, Garssen J, Dortant P, et al. Quercetin prevents UV-induced local immunosuppression, but does not affect UV-induced tumor growth in SKH-1 hairless mice. Photochem. Photobiol. 1997; 65:736-44.
54. Stewart LK, Wang Z, Ribnicky D, et al. Failure of dietary quercetin to alter the temporal progression of insulin resistance among tissues of C57BL/6J mice during the development of diet-induced obesity. Diabetologia. 2009; 52:514-23.
55. Utesch D, Feige K, Dasenbrock J, et al. Evaluation of the potential in vivo genotoxicity of quercetin. Mutat. Res. 2008; 654:38-44.
56. Vauzour D, Vafeiadou K, Rodriguez-Mateos A, et al. The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr. 2008; 3:115-26.
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