Quercetin has been called one of the most abundant antioxidant compounds in the diet. It is found in fruits, vegetables and grains, and its use has been linked to the amelioration of a number of chronic diseases.
In addition to its purported antioxidant capacity, research has shown that there is benefit to the use of quercetin in helping to reduce inflammation, reduce the symptoms of seasonal allergies, and even to manage blood pressure.
In the article below, we’ll explore the mechanisms by which quercetin may promote health- and lifespan.
Quercetin and its many roles in health and disease
The mechanism through which quercetin exerts its protective effect is not yet fully understood, however, current research shows that there is strong evidence that it is largely due to two mechanisms:
a) Regulation of oxidation effects
Research suggests that by reducing free radicals, quercetin has an effect on downregulation of the enzyme superoxide dismutase (SOD). SOD is produced to regulate these free radicals, however, when quercetin is in action, it balances out free radicals naturally, which reduces the need for SOD.
The mechanism has been well studied in animals, where quercetin has also been shown to balance chemical processes that are associated with multiple biological stress responses that affect our health- and lifespan, which provides strong supporting evidence that quercetin acts not only as a potent antioxidant but as a signal moderating compound (1).
There are multiple other studies that show how, as an antioxidant, quercetin plays a critical role in health and disease by exerting its effects on particular genes relating to lifespan outside of the SIRT1 pathway through which other flavonoids typically exert their effects (2).
b) Anti-inflammatory effects
Inflammation has a protective role in the body. It’s the body’s way of managing injury and is a process that promotes healing and repair; that’s when it’s managed well and does not continue for long periods of time. When inflammation is not down regulated after performing its function, it becomes chronic, and can have the opposite effect. This is when inflammation can begin to cause damage and disease. That’s where quercetin comes in. This compound has been shown to have an influence on both acute and chronic inflammation, with one of the best models to show this being arthritis.
We are eagerly awaiting further research that shows the effects of quercetin on various signalling pathways, one of the most exciting being its effect on hormesis, which is the activation of minor stress-response pathways that, at low doses, may have beneficial biological effects (3). For now, we’re interested in the antioxidant and anti-inflammatory effects that are known to have many benefits on health and disease.
A clinical trial conducted on women with rheumatoid arthritis (RA), published in 2017, reveals the significant anti-inflammatory effects of quercetin. After supplementing with 500mg a day for 8 weeks, when compared to the group taking a placebo, there were significant improvements in their overall clinical symptom scores and disease activity despite some participants still reporting tender and swollen joints. Researchers were able to pinpoint the mechanism of action to the predominant one at play in the etiology of RA, which is TNF-alpha, a highly inflammatory pathway (4).
Multiple studies have also been conducted in mice, which supports these results.
The most commonly used model for studying the pathways involved in the progression of arthritis in animals is called the collagen-induced arthritis (CIA) model. In a 2017 study, researchers studied the effects of quercetin in this model, comparing it to how traditional medications would fare against it’s natural, non-toxic effects. Interestingly, quercetin administered alone provided greater joint protection and suppressed joint inflammation the most even when compared to quercetin combined with methotrexate, a commonly used arthritic pharmaceutical drug (5).
Another popular model used to investigate the role of inflammation in mice who develop rheumatoid arthritis (RA), is by administering zymosan into their joints, which results in the pattern of pain and inflammation as is typically seen in RA patients. When mice with the zymosan-induced RA received quercetin, there was a dramatic improvement in their pain levels, they had reduced swelling and lower inflammatory compounds were detected in their joint cavities, suggesting that quercetin is a possible alternative therapy that can be used to treat arthritis (6).
There’s also hope for gout sufferers. Once again, studies conducted in mice have shown that quercetin offers a promising natural treatment for joint pain caused by gout. During the experiment, mice who had developed gout were given quercetin and their results were promising. Quercetin reduced pain, suppressed inflammatory chemical reaction in the joints, suppressed inflammatory pathways and decreased the production of free radicals. As has been noted in arthritis, quercetin appears to be an effective treatment for reducing the pain and inflammation of gout (7).
The main mechanisms of action of quercetin on allergic diseases involve its modulation of the branches of the immune system, acting as an antioxidant, inhibiting the release of histamine, and decreasing the production of pro-inflammatory cytokines. It has been suggested as being a natural therapy for bronchial asthma, allergic rhinitis and even peanut-induced allergic reactions (8).
The involvement of quercetin on true anaphylactic responses in an interesting one. An allergic reaction may cause potentially fatal responses by the immune system, which involves mast cell activation and the subsequent release of a number of chemical components, including histamine. We know that certain pharmaceutical drugs may cause an allergic reaction, which typically involves a significant effect from histamine. This type of allergic reaction is known as a pseudo-allergic response, and quercetin appears to have potent anti-pseudo-allergic effects. An in vivo study using a mouse model showed that after allergy-induced mast cell activation, quercetin down-regulated the release of histamine and other chemicals from mast cells. Additionally, it suppressed swelling that is typically induced by histamine release. In conclusion, the study noted that quercetin may be an effective treatment to use as a means to suppress pseudo-allergic related diseases (9).
Due to the growing burden of cancer and the high cost of treatment, in the last few years, research has turned to natural therapies, including food, to determine the potential of their anti-cancer properties in both the prevention and treatment of the disease. Quercetin is one of the food components that has been well-studied in a number of cancers. With the proven effects of quercetin as an antioxidant agent, it may offer action against cancer cells. Additional action on cancer has also shown quercetin to have an affect on inducing programmed cell suicide in cancer cells, a process known as apoptosis, which is ultimately the goal of any cancer therapy. Consideration for quercetins anti-inflammatory action in the prevention and treatment of cancer should also be taken into account.
Breast cancer is one of the most common forms of cancer in women, and while prognosis following treatment is fair, there is still a need to improve outcomes, particularly in the case of aggressive and malignant tumours. Studies in aggressive breast cancer cells have shown quercetin to influence apoptosis, reduce the ability of cancer cells to proliferate and suppress signalling pathways that exist between cancer cells (10).
In men, prostate cancer is one of the most common forms of cancer. As is the case with breast cancer, prognosis following diagnosis is typically fair, however, prevention and treatment of aggressive forms of prostate cancer still need to be expanded to improve outcomes. Due to the involvement of androgenic hormones in the mediation of the disease, antiandrogen therapies are currently used. One of the pathways involved in resistance to anti-androgenic treatment involves an increase in receptor splicing variants, such as AR-V7. It has been suggested that therapies to overcome this increase in AR-V7 are needed, which is where quercetin comes in. The splicing factor, hnRNPA1 that leads to the increased expression of AR-V7, has been demonstrated to be inhibited by quercetin. This means that quercetin, through its effect on hnRNPA1, could increase sensitization of cancer cells to new generation drugs as well as prolong their activity as a means to suppress further growth of these mutated cells (11).
It has been demonstrated that quercetin has potent antioxidant effects when taken in lower doses, in higher concentrations, however, may act as a pro-oxidant. The effects of quercetin as an antioxidant needs to consider the state of the cells and the concentration of quercetin used.
Neurological diseases such as Alzheimer’s and Parkinson’s disease
Neurological diseases place a significant amount of burden on community and healthcare alike. While treatment options that are currently available may be able to slow the progression of these diseases, such as Alzheimer’s and Parkinson’s, research has failed to provide the hope of a cure.
A large number of studies have investigated the role of quercetin in this regard, with most of the research being conducted using animal models or in cell cultures.
A study conducted in 2016 on neuronal cells showed that quercetin destabilizes abnormal proteins such as beta amyloids and tau, both hallmarks of the pathological process of the neurodegenerative disease Alzheimer’s. In addition, quercetin has been shown to increase the clearance of these proteins, and, in doing so, has the ability to improve cognition and memory during ageing (12). This mechanism was also previously shown in mice, where, in 2015, interventions with quercetin in an Alzheimer’s mouse model, provided evidence that suggested it may reverse the histological (tissue-related) hallmarks of the disease and protect cognitive and emotional function (13).
In addition to the localized benefits of quercetin on the ageing brain, benefits have also been seen in improved behavioural imbalances that are typical of the progression of neurological diseases, in particular Alzheimer’s (14).
Reduces risk of bacterial infections and supports host microbiome
Infections are a common cause of severe states of ill health and death. The toxic effects of many types of bacteria are well-known, and in the developing world, are particularly devastating. In well-established regions, bacterial infections and their treatment with antibiotics may give rise to resistant strains, and it is therefore essential to provide alternative treatments in the event that antibiotics fail to eradicate the infection. Studies in humans still need to be conducted into the effectiveness of quercetin in this regard, however, promising data presented from research conducted in cells and in mice is available.
In mice given a lethal dose of Streptococcus pneumoniae, the bacterial strain that is responsible for the majority of infectious pneumonia cases, treatment with quercetin not only improved their survival rate, it was shown to alleviate the lung tissue damage that this bacteria typically causes. Through anti-inflammatory mechanisms, quercetin suppressed release of chemicals involved in the production of lung fluid, and overall reduced the toxic effect of this disease (15).
Another area of interest is pathologies relating to perturbations of the gut microbiome. Disturbance between the bacteria in the gut and the host gives rise to inflammatory bowel conditions, which has great implications for overall health and disease. In mice, who have citrobacter-induced colitis, supplementation with quercetin at 30mg/kg appeared to relieve many of the symptoms of the condition by mediating inflammatory pathways, and promoting release of anti-inflammatory compounds that protect the colonic tissue from the damaging effects of the bacteria. Additionally, quercetin was shown to enhance commensal bacteria, thus improving diversity of healthful populations, which further reduced gut inflammation (16).
Coronary heart disease (CHD) is one of the leading causes of death around the globe. There is, however, promising evidence coming out of clinical trials on the effect of quercetin on heart disease and how it may be used as a therapy in protecting the heart from further damage following the diagnosis of CHD.
One study grouped 85 patients with stable CHD into a treatment and a comparison branch. The treatment group received 120mg of quercetin daily, which was added to their standard treatment routine. Those in the comparison group received their regular treatment only. While both groups showed improvement in multiple markers of CHD, the quercetin group outshone the comparison group in its cardioprotective ability (17).
Another study, this time in patients with acute decompensated heart failure (ADHF), quercetin showed its ability to improve left ventricular contraction, which reduces the severity of heart failure in this subset of patients. Even low doses of quercetin were suggested as being effective in this regard (18).
A review of the multiple effects on quercetin suggests that it may reduce the effect of cholesterol oxidation through its antioxidant activity, improve blood pressure by increasing flexibility of artery cell walls, reduce the risk of inflammation and collection of plaques, and reduce damage to the nerve cells that control heart function. It is due to these numerous benefits that multiple studies have concluded that quercetin is a promising therapeutic adjunct in the treatment of heart disease (19).
Anti Aging and longevity
Using the well-established worm model Caenorrhabiditis elegans, back in 2007, researchers began exploring this hormetic effect of quercetin in this organism. Under thermal stress that typically significantly impacts the lifespan of C. elegans, quercetin offered increased resistance to stress and induced positive chromosomal changes (20).
Then again, performing complementary work in 2008, the same group hoped to elucidate other protective effects of quercetin that have been shown to be true in in vitro studies. When they administered quercetin again to C. elegans, the evidence for a 15% increase in lifespan pointed to the strong free radical scavenging potential of quercetin.
The DAF-16 pathway is yet another gene of interest in longevity, and it is a sequence preserved across multiple species, including humans. In 2008, however, when researchers used C. elegans worms that had been manipulated to possess no DAF-16 genes, there was still a mean increase in their lifespan of 15%. Additionally, there was enhanced resistance to both thermal and oxidative stress in these mutant worms, which shows that quercetin elicits its effects independently of the DAF-16 pathway (21).
Another well-established model of study, used to observe the mechanistic effects of compounds, is the common fruit fly, D. melanogaster. In 2016, administering quercetin for 10 days was shown to improve both the average and maximum lifespan in female flies. What’s more, is that researchers observed that this intervention also improved their motility, increased their resistance to the effects of oxidative stress, and offered protection against gamma radiation, even though the protective effects for the latter were short-lived (22).
Senescent cells in humans have been shown to accumulate during the process of ageing, which is strongly associated with dysfunction of multiple biological systems (23). Using a mouse model. More recent research conducted in 2018, the effects of quercetin combined with the chemical compound dasatinib (a drug targeting ageing) was tested on senescent cells. Even when administered intermittently, the intervention improved physical fitness of the mice while improving their survival rate by 36%. There was a combined reduction of 65% in their mortality hazard score, which shows both the health- and life-span enhancing effects of the combination of quercetin and dasatinib (24).
Further expansion by researchers in 2018, into the role of quercetin on longevity, revealed there is an underlying mechanism through which quercetin promotes homeostasis in reactive oxygen species (ROS) and inflammation. Podospora anserina, a fungus, has been frequently used in research to study pathways involved in the ageing process. In this particular study, quercetin was administered to the organisms in a normal physiological environment as well as that in which a SAMe-dependent methylation pathway (PaMth1) had been removed. This PaMth1 gene is necessary for the conversion of a specific group of polyphenol compounds, including quercetin, into their active form and is a pathway translated to humans, rodents and other species (25). The increase in lifespan noted in normal physiological conditions and not in PaMth1 deleted ones suggests that it is through this methylation pathway that quercetin may induce its effects on ROS (26).
A review of multiple studies to explain the effects of the different types of flavonoids on lifespan was conducted in 2017, where nine of the studies provided information about quercetin having been used in flies, worms and mice. Of those nine studies, seven provided positive correlation between the use of quercetin and an increase in lifespan (27). The two studies that could not detect a change in lifespan with the intervention, where one found a decrease in lifespan of C. elegans with the use of quercetin at very high molecular quantities, possibly due to the pro-oxidant effects of flavonoids in significantly higher doses (28).
Clinical trials are needed, but in vitro studies provide us with some clues
We are eagerly awaiting further research that shows the effects of quercetin on various signalling pathways, one of the most exciting being its effect on hormesis, which is the activation of minor stress-response pathways that, at low doses, may have beneficial biological effects (29). For now, we’re interested in the antioxidant and anti-inflammatory effects that are known to have many benefits on health and disease.
While human cell cultures have been used to assess the effects of quercetin, it is noteworthy to mention that we are continuing to monitor research for the effects conducted in clinical trials, where they can be observed under biological conditions in humans.
Cells do, however, provide a certain level of evidence of function. For example, in one study, conducted in 2012, evidence was obtained to show that in neuronal cells, the addition of quercetin enhanced their performance by a reduction in the toxicity induced by alterations in sugar balance. Improved culture longevity was observed in quercetin treated cultures when compared to controls (30).
With the research that we do currently have access to, we believe quercetin offers a promising natural compound, that when administered at specific concentration, it may mediate inflammation and moderate reactive oxygen species. These processes are typical of biological function and take place in the body every day; unfortunately, when they are not regulated, they can lead to disease and the effects we know as ageing. Combining quercing with other polyphenol compounds that act on different pathways that influence health and disease, we see real promise in its ability to not only help us to live longer, but to live healthier, too.
Selection of studies used for this article:
- Kampkotter, A., et al. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp Biochem Physiol B Biochem Mol Biol. 2008 Feb;149(2):314-23.
- Pietsch, K., et al. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009 Oct;10(5):565-78.
- Mattson MP (2008) Dietary factors, hormesis and health. Age-ing Res Rev 7:43–48.
- Javadi, F., et al. The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial. J Am Coll Nutr. 2017 Jan;36(1):9-15.
- Haleagrahara, N., et al. Therapeutic effect of quercetin in collagen-induced arthritis. Biomedicine & Pharmacology. 2017. 90:38-46.
- Guazelli, C., et al. Quercetin attenuates zymosan-induced arthritis in mice. Biomedicine & Pharmacology. 2018. (102):175-184.
- Ruiz-Miyazawa, K., et al. Quercetin inhibits gout arthritis in mice: induction of an opioid-dependent regulation of inflammasome. Inflammopharmacology. 2017. 25:555–570.
- Mlcek, J., et al. Quercetin and Its Anti-Allergic Immune Response. Molecules. 2016. 21(5):623.
- Ding, Y., et al. Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R related Ca2+ fluctuations. International Immunopharmacology. 2019. 66:185-197.
- Ezzati, M., et al. A review on anti-cancer properties of Quercetin in breast cancer. 2020. Life Sciences, 117463.
- Tummala, R., et al. Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells. Molecular Cancer Therapeutics. 2017. 16(12).
- Sugathy, N., et al. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomed Pharmacother. 2016 Dec;84:892-908.
- Sabogal-Guaqueta, A., et al. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology. 2015 Jun;93:134-45.
- Amanzadeh, E., et al. Application of quercetin in neurological disorders: from nutrition to nanomedicine. 2019. Reviews in the Neurosciences, 0(0).
- Lv, Q., et al. Quercetin, a pneumolysin inhibitor, protects mice against Streptococcus pneumoniae infection. Microbial Pathogenesis. 2020. 140:103934.
- Lin, R., et al. Dietary Quercetin Increases Colonic Microbial Diversity and Attenuates Colitis Severity in Citrobacter rodentium-Infected Mice. Front Microbiol. 2019; 10: 1092.
- Chekalina, N., et al. Effect of quercetin on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease. Wiadomosci Lekarskie (Warsaw, Poland : 1960). 2017;70(4):707-711.
- Kozhukhov, S., & Parkhomenoko, A. Multicenter randomized clinical trial of the efficacy and safety of intravenous Quercetin in patients with acute decompensated heart failure. Heart Failure Conference. 2019.
- Patel, R., et al. Therapeutic potential of quercetin as a cardiovascular agent. European Journal of Medicinal Chemistry. 2018. 155:889-904.
- Kampko¨tter A, Nkwonkam CG, Zurawski RF, Timpel C, Cho-volou Y, Wa¨tjen W, Kahl R (2007) Investigations of pro-tective effects of the ﬂavonoids quercetin and rutin onstress resistance in the model organism Caenorhabditiselegans. Toxicology 234:113–123.
- Saul, N., et al. Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved? Mech Ageing Dev. 2008 Oct;129(10):611-3.
- Proshkina E, Lashmanova E, Dobrovolskaya E, Zemskaya N,Kudryavtseva A, Shaposhnikov M, Moskalev A (2016) Geroprotective and radioprotective activity of quercetin, (-)-epicatechin and ibuprofen in Drosophila melanosgaster.Front Pharmacol 7:505.
- Farr JN., et al. (2017)Targeting cellular senescence prevents age-related boneloss in mice. Nat Med 23:1072–1079.
- Xu, M., et al. (2018) Senolytics improve physical functionand increase lifespan in old age. Nat Med 24:1246–1256.
- Averbeck, N. B., Jensen, O. N., Mann, M., Schägger, H., and Osiewacz, H. D. (2000). Identification and characterization of PaMTH1, a putative O-methyltransferase accumulating during senescence of Podospora anserina cultures. Curr. Genet. 37, 200–208.
- Warnsmann, V., et al. Quercetin-Induced Lifespan Extension in Podospora anserina Requires Methylation of the Flavonoid by the O-Methyltransferase PaMTH1. Front. Genet., 04 May 2018.
- Pallauf, K., et al. A literature review of flavonoids and lifespan in model organisms. Proceedings of the Nutrition Society (2017), 76, 145–162.
- Pietsch, K., et al. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011 Aug;12(4):329-47.
- Mattson MP (2008) Dietary factors, hormesis and health. Age-ing Res Rev 7:43–48.
- Niklas, J., et al. Quercetin treatment changes fluxes in the primary metabolism and increases culture longevity and recombinant α₁-antitrypsin production in human AGE1.HN cells. Appl Microbiol Biotechnol. 2012 Apr;94(1):57-67.