Quercetin
Quercetin's Potential in PV and MPNs
Emerging research suggests that quercetin, a naturally occurring flavonoid, may hold therapeutic promise for polycythemia vera (PV) and other myeloproliferative neoplasms (MPNs). While clinical trials specifically in PV/MPN patients are lacking, a growing body of preclinical evidence warrants further investigation into quercetin's potential as a complementary treatment.
1. JAK2 Inhibition: In Silico and Preclinical Evidence
In silico (computer-based) molecular docking studies have identified quercetin as a potential natural JAK2 inhibitor, with predicted binding affinities in the nanomolar range (Potential JAK2 Inhibitors from Selected Natural Compounds, 2024). This suggests that quercetin may directly interfere with JAK2 activity, a key driver of MPN pathogenesis.
Numerous in vitro and in vivo studies have demonstrated quercetin's ability to inhibit the JAK/STAT pathway directly or indirectly in various cancer types and tissue models. These include:
Liver cancer (Wu et al., 2019).
Cervical cancer (Luo et al., 2016).
Photoaging in human skin (Shin et al., 2019).
Vascular smooth muscle cells (Wang et al., 2022).
Sjögren's syndrome (Chang et al., 2022).
Osteosarcoma (Jing et al., 2022).
Endothelial cells (Choi et al., 2009).
Keratinocytes (Lee et al., 2018).
Liver protection (Ghosh et al., 2022).
Autoimmune encephalomyelitis (Muthian & Bright, 2004).
Kidney (Hu et al., 2012).
Melanoma (Cao et al., 2014).
Lung injury (Tang & Yang, 2016).
Endothelial cells (Wang et al., 2019).
Glioblastoma (Michaud-Levesque et al., 2012).
Shows anti-AML and anti-MDS effects that aren’t mediated by JAK/STAT (Torello et al 2021)
2. Targeting Myelofibrosis
A single case report described successful management of myelofibrosis (MF) using a multi-component regimen that included quercetin (1000 mg twice daily) [A case of myelofibrosis controlled, 2017]. Notably, the patient's transfusion dependence decreased significantly after switching to a more bioavailable form of quercetin. The authors hypothesized that quercetin's ability to lower TGF-β levels, a key driver of fibrosis, and inhibit the JAK/STAT pathway contributed to the observed improvement.
3. Potentiating Interferon-α
Quercetin has been shown to enhance the antiproliferative effects of interferon-α (IFN-α), a common MPN treatment, in hepatocellular carcinoma cells [Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells, 2017]. This enhancement was mediated by quercetin's inhibition of SHP2 phosphatase, leading to increased activation of the JAK/STAT pathway. These findings suggest a potential for synergistic effects when combining quercetin with IFN-α in MPN therapy, although this requires clinical validation.
4. Hepcidin Induction and Iron Regulation
Quercetin, along with other polyphenols, has been found to induce hepcidin, the master regulator of iron homeostasis, in both cell and animal models (Small Molecule Hepcidin Inducers, Katsarou-2018, Hawula-2019). Hepcidin induction occurs via activation of the Nrf2 pathway and subsequent binding to an antioxidant response element in the hepcidin (HAMP) gene promoter. Since dysregulated iron metabolism is a feature of PV, quercetin's ability to modulate hepcidin could theoretically help control red blood cell production. However, this hypothesis needs to be tested in PV-specific models and clinical trials.
Safety, Tolerability, and Lifespan Effects:
1. Safety in Animal Models
A 14-week sub-chronic oral toxicity study in mice demonstrated that quercetin, at doses ranging from 62 to 250 mg/kg of diet, did not cause any significant toxicity, organ damage, or alterations in behavior or metabolism (Sub-chronic oral toxicity screening of quercetin in mice, 2022).
These findings suggest a relatively wide safety margin for quercetin in mice at doses that have shown efficacy in preclinical cancer models.
2. Lifespan and Healthspan in Mice: Mixed Findings
The effects of quercetin on lifespan in mice appear to be complex and dependent on dose, sex, and the presence of other dietary factors.
A study using a low dose of quercetin (0.125 mg/kg weekly) found improvements in several healthspan markers, including exercise endurance and cardiac function, in aged mice. However, this regimen did not significantly extend maximum lifespan (Low-dose quercetin positively regulates mouse healthspan, 2019).
In contrast, an older study reported that a high dietary dose of quercetin (0.1%) significantly reduced the lifespan of "shorter-living" male mice (Quercetin, flavonoids and the life-span of mice, 1982).
However, in the same study, a blackcurrant juice extract containing a mixture of flavonoids, including quercetin, prolonged the lifespan of "longer-living" female mice.
These findings highlight the importance of considering dose, sex, and potential interactions with other dietary components when evaluating quercetin's effects on lifespan. They also suggest that the optimal dose for health benefits may be lower than previously thought and that very high doses could have detrimental effects.
Important Considerations and Future Directions
Clinical Trials Needed: While the preclinical data are promising, it is crucial to emphasize that clinical trials specifically investigating quercetin's efficacy and safety in PV/MPN patients are currently lacking.
Bioavailability and Formulation: Quercetin's bioavailability can be a limiting factor. Research into optimized formulations, such as the "caged molecule" form mentioned in the myelofibrosis case report, is needed to enhance absorption and delivery.
Dosage Optimization: The optimal dosage of quercetin for MPN patients remains to be determined. The mixed findings on lifespan in mice underscore the need for careful dose-ranging studies in humans.
Potential Drug Interactions: Quercetin can interact with certain medications, particularly those metabolized by CYP enzymes. Patients considering quercetin supplementation should consult with their healthcare providers to avoid potential adverse interactions.
Combination Therapies: The potential for synergistic effects between quercetin and existing MPN therapies, such as IFN-α or JAK inhibitors, warrants further investigation.
Conclusions
Quercetin exhibits a range of properties that make it a compelling candidate for further research in PV and other MPNs. Its potential to inhibit JAK2, modulate hepcidin, reduce inflammation, and enhance the efficacy of other treatments, combined with its relatively good safety profile in animal studies, provides a strong rationale for clinical investigation. However, it is essential to proceed cautiously, with a focus on rigorous clinical trials to determine quercetin's true efficacy, optimal dosage, and long-term safety in the context of MPN management. Patients should always consult their healthcare team before adding any supplements to their treatment plan.
Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients (2024)
Potential JAK2 Inhibitors from Selected Natural Compounds
Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases (2022)
Quercetin as a JAK-STAT Inhibitor in Cancer
Quercetin reduced proliferation, invasion, and metastasis in many cancer cell lines by inhibiting JAK-STAT. Cancers include glioblastoma, HCC, gastric, breast, pancreatic, and lung.
In glioblastoma cells, 25-50 μM quercetin inhibited IL-6-induced STAT3 activation. This reduced proliferation and invasion.
In HCC, quercetin enhanced IFNα-induced gene expression by activating STAT1. It also reduced STAT3 activation and metastasis.
In breast cancer, quercetin and docetaxel synergistically inhibited growth and activated apoptosis by inhibiting STAT3 and other pathways.
In pancreatic cancer, quercetin prevented EMT and metastasis by inhibiting IL-6-induced STAT3 activation.
In lung cancer with constitutive STAT3 activation, quercetin triggered apoptosis by inhibiting IL-6-STAT3 signaling.
Quercetin as a JAK-STAT Inhibitor in Neurodegenerative Diseases
The JAK-STAT pathway mediates neuroinflammation in diseases like Alzheimer's, Parkinson's, and multiple sclerosis. Inhibiting it reduces neuronal damage.
In multiple sclerosis models, quercetin reduced brain inflammation and demyelination markers by inhibiting STAT3 activation.
In Parkinson's models, quercetin improved symptoms and reduced neuroinflammation by inhibiting STAT pathway activators like IL-6.
In Alzheimer's models, quercetin inhibited STAT activation and reduced amyloid beta aggregation and neurotoxicity.
Polyphenolic Flavonoid Compound Quercetin Effects in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes (2021)
Antiproliferative activity: Quercetin inhibits cell proliferation and induces cell cycle arrest at G1 or G2/M phase in AML and MDS cell lines by modulating cyclins, CDKs, CDK inhibitors, and Rb phosphorylation.
Apoptotic activity: Quercetin induces apoptosis in AML and MDS cells through both the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. It modulates pro- and anti-apoptotic proteins like Bcl-2 family members, releases cytochrome c, activates caspases, and induces DNA fragmentation.
Autophagic activity: Quercetin triggers protective autophagy in AML and MDS cells by affecting PI3K/Akt/mTOR and other autophagy-related signaling pathways. However, autophagy inhibition can promote quercetin-induced apoptosis.
Antioxidant activity: Quercetin acts as an antioxidant by scavenging reactive oxygen species (ROS). It reduces oxidative stress in AML and MDS cells, which may help limit DNA damage and mutations.
Epigenetic modulation: Quercetin inhibits DNA methyltransferases and histone deacetylases, leading to demethylation and increased expression of pro-apoptotic genes in AML cells.
Organs and situations where Quercetin was shown to induce health promoting effects by interacting (mostly inhibiting) the JAK/STAT pathway
Liver cancer: Quercetin inhibited proliferation and induced apoptosis in hepatocellular carcinoma cells by downregulating JAK2/STAT3 signaling (Wu et al., 2019).
Cervical cancer: Quercetin nanoparticles suppressed cervical cancer progression by inhibiting JAK2 and inducing apoptosis and autophagy (Luo et al., 2016).
Photoaging in human skin: Quercetin prevented UV-induced skin aging by directly inhibiting JAK2 (Shin et al., 2019).
Vascular smooth muscle cells: Quercetin inhibited angiotensin II-stimulated vascular smooth muscle cell proliferation by suppressing JAK2/STAT3 activation (Wang et al., 2022).
Sjögren's syndrome: Quercetin protected against salivary gland damage in Sjögren's syndrome by regulating OB-R/JAK2/STAT3 signaling (Chang et al., 2022).
Osteosarcoma: Quercetin inhibited osteosarcoma proliferation and immune escape by inhibiting JAK2 through its JH2 domain (Jing et al., 2022).
Endothelial cells: Quercetin inhibited oxidized LDL-induced endothelial apoptosis by modulating JAK2-STAT3 pathway (Choi et al., 2009).
Keratinocytes: Quercetin inhibited IL-18 secretion in keratinocytes by downregulating JAK2/STAT1 pathway (Lee et al., 2018).
Liver protection: Quercetin showed hepatoprotective effects by inhibiting cell signaling proteins like JAK2 (Ghosh et al., 2022).
Autoimmune encephalomyelitis: Quercetin ameliorated experimental autoimmune encephalomyelitis by inhibiting JAK-STAT pathway and Th1 cell differentiation (Muthian & Bright, 2004).
Kidney: Quercetin blocked NLRP3 inflammasome activation and improved impaired JAK2/STAT3 signaling in kidneys of fructose-fed rats (Hu et al., 2012).
Melanoma: Quercetin inhibited melanoma progression by suppressing STAT3 signaling (Cao et al., 2014).
Lung injury: Quercetin ameliorated LPS-induced acute lung injury in rats by inhibiting JAK2/STAT3 signaling (Tang & Yang, 2016).
Endothelial cells: Quercetin inhibited angiogenesis in endothelial cells by suppressing JAK2/STAT3 and PI3K/AKT pathways via decreasing miR-216a (Wang et al., 2019).
Glioblastoma: Quercetin inhibited glioblastoma growth and migration by abrogating IL-6 induced STAT3 signaling (Michaud-Levesque et al., 2012).
Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase (2017)
Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-α-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-α on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-α-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-α-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-α on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.
A case of myelofibrosis controlled (2017)
“Fibrosis” begins with excessive deposition of extracellular matrix. That can evolve to fibrosis/scar tissue & considered cause of most organ failure
It is driven by excessive transforming growth factor beta and can involve genetic and epigenetic factors in the action pathway. The condition can be reversed, if TGF-beta production is decreased.
Initial thought was to treat myelofibrosis as fibrosis problem because of the failure from other therapy
Agents that lower TGF-β
Epigallocatechin gallate (EGCG) - Taurine
Metformin - Berberine
Curcumin - Quercetin
N-acetylcysteine - Lycopene
Silymarin - Glycyrrhiza
Cod liver oil - Ascorbic acid
Boswellic acids - Astaxanthin
Vitamin D - Hesperetin
Caffeine - Hesperidin
Phytolacca - Vitamin B6
References are available on PubMed
Treatment program
From physical signs of malabsorption and the low immune system, patient placed on GFD w/o test
Metformin-ER 500 mg bid – several anti-malignant actions, including in the hematopoietic area, can decrease cell proliferation encouraged by mTOR, and attenuate organ fibrosis
Berberine 500 mg bid - contributes to lowering the mTOR pathway implicated in myelofibrosis.
Quercetin 1000 mg bid – (Note: Transfusion frequency dramatically decreased after replacement by a highly absorbed form [caged molecule by Tesseract], approx. 100% delivery of 105 mg) Quercetin has many anti-cancer mechanisms. Known to lower TGFbeta and reduce fibrosis. Quercetin can inhibit the JAK/STAT cascade of inflammation and cell proliferation
Astaxanthin, 12 mg bid – quenches hydroxyl radical and possibly slows further DNA mutation
Vitamin K2 (15 mg daily as MK4) for sub-skin bleeding, due to platelets of 70
PubMed search - this seems the 1st report controlling myelofibrosis with refractory anemia (other than stem cell transplantation) and by mostly non-Rx agents.
Small Molecule Hepcidin Inducers (Katsarou-2018, Hawula-2019)
Hepcidin is a master regulator of iron. Hepcidin mimetic Rusfertide is being tested successfully as a PV treatment (Phase III). Luckily, there are natural inducers of hepcidin.
8.3. Small Molecule Hepcidin Inducers
Several polyphenolic small molecules or phytoestrogens that are found in fruits and vegetables likewise induced hepcidin in HepG2 cells and in rats. These include resveratrol, quercetin, kaemferol, naringenin, epi-gallo-catechin-3-gallate, and operate by activating Nrf2 for binding to an antioxidant response element (ARE) in the HAMP promoter [78].
Sub-chronic oral toxicity screening of quercetin in mice (2022)
Background
Quercetin is an organic flavonoid present in several fruits and vegetables. The anti-inflammatory, antiviral, antioxidant, cardio-protective, anti-carcinogenic and neuroprotective properties demonstrated by this dietary supplement endorses it as a possible treatment for inflammatory diseases and cancer. Unfortunately, conflicting research has cast uncertainties on the toxicity of quercetin. The main purpose of this study was to determine if quercetin has any toxic properties in mice at doses that have shown efficacy in pre-clinical studies regarding cancer, cancer therapy, and their off-target effects.
Methods
A sub-chronic toxicity study of quercetin was examined in male and female CD2F1 mice. Three different doses of quercetin (62, 125, and 250 mg/kg of diet) were infused into the AIN-76A purified diet and administered to mice ad libitum for 98 days. Body weight (BW), food consumption, water intake, body composition, blood count, behavior, and metabolic phenotype were assessed at various timepoints during the course of the experiment. Tissue and organs were evaluated for gross pathological changes and plasma was used to measure alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT).
Results
We found that low (62 mg/kg of diet), medium (125 mg/kg of diet), and high (250 mg/kg of diet) quercetin feeding had no discernible effect on body composition, organ function, behavior or metabolism.
Conclusions
In summary, our study establishes that quercetin is safe for use in both female and male CD2F1 mice when given at ~ 12.5, 25, or 50 mg/kg of BW daily doses for 14 weeks (i.e. 98 days). Further studies will need to be conducted to determine any potential toxicity of quercetin following chronic ingestion.
Low-dose quercetin positively regulates mouse healthspan (2019)
A recent study by Geng et al. (2018) found that long-term, low-dose quercetin (Que) monotherapy (0.125 mg/kg weekly for 8 months) improved multiple aspects of healthspan including exercise endurance, cardiac function, adipose tissue aging, and inflammation in aged mice, without extending maximal lifespan. These beneficial effects were associated with stabilized heterochromatin architecture and repression of retrotransposable elements like L1 in senescent stem cells and tissues, rather than major changes in protein-coding genes. In contrast to previous senolytic regimens using high-dose Que, low-dose Que alone acted through a senostatic mechanism to attenuate aging phenotypes in mice. This study suggests low-dose Que monotherapy may have translational potential as a geroprotective strategy, with advantages over high-dose combinations including reduced side effects and avoiding drug interactions. Further research is needed to confirm the mechanisms and effects in other model organisms. Overall, this work reveals a role for low-dose Que in stabilizing heterochromatin, inhibiting retrotransposon activation, reducing inflammation, and improving healthspan in aged mice.
QUERCETIN, FLAVONOIDS AND THE LIFE-SPAN OF MICE (1982)
A dietary supplement of 0.1% quercetin significantly reduced the life span of mice. The
effect was predominantly on the 'shorter living' males. A blackcurrant juice extract, containing a mixture of flavonoids in addition to quercetin, prolonged significantly the life span of the 'older dying' females. The significance of these results vis-a-vis aging mechanisms and the dietary intake of quercetin is discussed.
For an avg human: 2kg food/day => 2g Quercetin / day
Experimental Gerontology: Quercetin, Flavonoids, and the Life-Span of Mice
Abstract
This study, conducted by Eleri Jones and R.E. Hughes at the University of Wales Institute of Science and Technology, investigated the effects of dietary quercetin and a blackcurrant juice extract, rich in flavonoids, on the lifespan of mice. The findings revealed that a dietary supplement of 0.1% quercetin significantly reduced the lifespan of mice, particularly affecting the shorter-living males. Conversely, the blackcurrant juice extract, containing a mixture of flavonoids including quercetin, significantly prolonged the lifespan of the longer-living females. The study discusses the implications of these results in the context of aging mechanisms and dietary quercetin intake.
Introduction
Quercetin, a pentahydroxyflavone, and its glycosides, such as rutin, are widely distributed in plants. Despite their presence in the human diet, their metabolic significance remains largely unknown. Previous research has suggested that quercetin may influence cholesterol metabolism in animals and modify tissue ascorbic acid concentration in guinea pigs. However, recent in vitro studies have raised concerns about quercetin's direct mutagenicity, potentially impacting human nutrition. This study aimed to explore the effects of quercetin and other dietary flavonoids on the lifespan of mice.
Methods
Three groups (A, B, C) of 5-week-old mice (strain LACA, Medical Research Council) were used, each comprising 50 males and 50 females.
Group A (Control): Received a standard semi-synthetic diet (MG1), designed to be scorbutogenic and virtually flavonoid-free.
Group B (Blackcurrant): Received MG1 supplemented with 'single strength' blackcurrant juice concentrate (220 ml juice per 1000 g diet), providing an estimated 380 mg of total flavonoids, including approximately 40 mg of quercetin and its glycosides, with the remainder mainly anthocyanins.
Group C (Quercetin): Received MG1 supplemented with 0.1% quercetin, providing an estimated daily intake of about 10 mg quercetin per animal.
Citric acid and ascorbic acid were added to diets A and B to match the quantities introduced into diet C by the blackcurrant juice concentrate, as previous studies had shown that high dietary citric acid intake could influence mouse lifespan.
Results
Body Weight and Food Intake:
No significant differences were observed in food intake between the groups. Similarly, there were no significant differences in the time taken to attain a stable mature body weight (Table 1).
Lifespan:
Quercetin (Group C): A significant overall reduction in lifespan was observed in the quercetin-supplemented group compared to the control group (Fig. 1, Table 2). This effect was primarily attributed to the male mice and was more pronounced in the shorter-living males. The lifespan of the 15 longest-living animals remained unaffected by quercetin.
Blackcurrant Juice Concentrate (Group B): No significant effect on the mean overall lifespan was observed. However, a significant prolongation of lifespan was noted in the 15 longest-living females (Table 2, Fig. 2).
Discussion
Quercetin's Effect on Lifespan:
The reduction in lifespan observed in the quercetin-supplemented group was unexpected, as quercetin's antioxidant properties and ability to stabilize ascorbic acid might theoretically suggest a potential for lifespan extension. Antioxidants, by scavenging free radicals, have been shown to increase the lifespan of experimental animals in some studies. Additionally, quercetin's role in retarding the chemical degradation of ascorbic acid, potentially reducing the formation of mutagenic breakdown products, could theoretically contribute to retarding the aging process.
However, the study's findings suggest that these potential benefits of quercetin might be overshadowed by less advantageous attributes. The observed reduction in lifespan aligns with reports of quercetin's relatively high mutagenicity in in vitro tests, potentially supporting a somatic mutation theory of aging.
Another possible contributing factor could be tissue deprivation of trace elements. Quercetin's ability to chelate with certain metals, such as copper, could lead to a chronic deficiency of essential elements, potentially contributing to a reduced lifespan. A similar mechanism has been proposed to explain the reduced lifespan of mice receiving elevated dietary intakes of citric acid.
Blackcurrant Extract's Effect on Lifespan:
The blackcurrant extract, in contrast to quercetin alone, exhibited a different effect, prolonging the lifespan of the longer-living females. This suggests a distinct mode of action and aligns more closely with theoretical expectations based on the antioxidant properties of flavonoids. Quercetin is a relatively minor component of the blackcurrant juice flavonoid complex, and its potentially deleterious activity might be masked by the beneficial influence of other flavonoids present.
Differential Effects on 'Early Dying' and 'Late Dying' Mice:
Analysis of deaths in terms of 'early dying' and 'late dying' mice revealed a qualitative difference between the effects of the two dietary supplements. Quercetin primarily affected the lifespan of the 'early dying' animals, while the blackcurrant extract's effect was predominantly observed in the 'late dying' animals. This suggests that quercetin might exert chronic toxicity, preferentially affecting animals predisposed to shorter lifespans due to constitutional reasons. In contrast, the blackcurrant extract might have a 'true' lifespan effect, primarily impacting animals genetically predisposed to longevity.
This distinction echoes the concept proposed by Clarke and Maynard-Smith, who differentiated between aging per se and a reduced 'threshold of vitality.' Analyzing lifespan studies in terms of 'early dying' and 'late dying' groups could help distinguish between 'prolongation of living' and 'prevention of death.'
Human Implications:
The study's findings have potential implications for human nutrition. Quercetin is widely distributed in the plant kingdom, with varying concentrations in different fruits and vegetables. However, it is often concentrated in the outer, non-edible layers, while the more commonly consumed fleshy parts contain relatively lower amounts.
The per capita daily intake of quercetin in the average diet is estimated to be around 50 mg. However, individuals who consume large amounts of salads, unpeeled fruits and vegetables, and 'natural food' products might ingest significantly higher amounts, potentially reaching 200-500 mg daily.
Detailed Analysis and Interpretation:
1. Quercetin's Mutagenicity and Somatic Mutation Theory of Aging:
The study's findings align with the growing body of evidence suggesting that quercetin possesses mutagenic properties. In vitro studies using bacterial and mammalian cell systems have demonstrated quercetin's ability to induce mutations. This mutagenicity could potentially contribute to the accumulation of somatic mutations over time, a process implicated in the aging process according to the somatic mutation theory of aging.
The somatic mutation theory posits that aging results from the gradual accumulation of DNA damage and mutations in somatic cells, leading to cellular dysfunction and ultimately, organismal decline. Quercetin's mutagenic activity could accelerate this process, leading to a shortened lifespan, as observed in the study.
2. Chelation and Trace Element Deficiency:
Quercetin's ability to chelate with metal ions, such as copper, could potentially lead to trace element deficiencies. Copper is an essential trace element involved in various physiological processes, including enzyme activity, connective tissue formation, and immune function. Chronic copper deficiency could have detrimental effects on health and potentially contribute to a reduced lifespan.
The study's authors suggest that a similar mechanism might explain the reduced lifespan observed in mice receiving high dietary intakes of citric acid. Citric acid, like quercetin, is a chelating agent and could potentially interfere with the absorption and utilization of essential trace elements.
3. Antioxidant Properties and Free Radical Scavenging:
Quercetin is a potent antioxidant, capable of scavenging free radicals and protecting cells from oxidative damage. Free radicals are highly reactive molecules that can damage cellular components, including DNA, proteins, and lipids. Oxidative damage is implicated in various age-related diseases and is thought to contribute to the aging process.
Theoretically, quercetin's antioxidant properties should protect against oxidative damage and potentially extend lifespan. However, the study's findings suggest that this potential benefit might be outweighed by other factors, such as mutagenicity and chelation.
4. Interaction with Ascorbic Acid:
Quercetin has been shown to stabilize ascorbic acid (vitamin C), retarding its chemical degradation. Ascorbic acid is an essential nutrient with antioxidant properties and plays a crucial role in various physiological processes. Breakdown products of ascorbic acid have been shown to be mutagenic in some studies.
By stabilizing ascorbic acid, quercetin could potentially reduce the formation of these mutagenic breakdown products, theoretically contributing to a healthier lifespan. However, the study's results suggest that this effect might not be sufficient to counteract the negative effects of quercetin observed in this particular experimental setup.
5. Blackcurrant Extract and the Role of Other Flavonoids:
The blackcurrant extract, which contains a mixture of flavonoids including quercetin, exhibited a different effect compared to quercetin alone. This suggests that the other flavonoids present in the extract might play a significant role in modulating quercetin's effects.
Anthocyanins, the major flavonoid components of the blackcurrant extract, are also potent antioxidants and have been associated with various health benefits. It is possible that the antioxidant and potentially anti-mutagenic properties of anthocyanins and other flavonoids in the extract counteract the negative effects of quercetin, resulting in the observed lifespan extension in the longer-living females.
6. Differential Effects on Males and Females:
The study found that quercetin's negative effects were primarily observed in male mice, while the blackcurrant extract's positive effects were seen in females. This suggests potential sex-specific differences in the metabolism or sensitivity to flavonoids.
Further research is needed to elucidate the mechanisms underlying these sex-specific differences. Hormonal factors, differences in gut microbiota composition, and variations in metabolic pathways could potentially contribute to the observed differences.
7. 'Early Dying' vs. 'Late Dying' Mice:
The distinction between 'early dying' and 'late dying' mice provides valuable insights into the potential mechanisms of action of the two dietary supplements. Quercetin's preferential effect on the 'early dying' animals suggests that it might exert chronic toxicity, exacerbating existing weaknesses or vulnerabilities in these animals.
On the other hand, the blackcurrant extract's effect on the 'late dying' animals suggests a potential 'true' lifespan effect, possibly by protecting against age-related decline in animals genetically predisposed to longevity.
8. Limitations of the Study:
Mouse Model: The study was conducted using a specific strain of mice, and the results might not be directly applicable to other strains or species, including humans.
Dietary Composition: The use of a semi-synthetic diet might not fully reflect the complexity of a typical human diet.
Dose: The study used a specific dose of quercetin, and the effects might vary at different doses.
Duration: The study's duration was limited to the lifespan of the mice, and longer-term effects are unknown.
Mechanism of Action: The study did not definitively determine the precise mechanisms underlying the observed effects.
Quercetin is a flavonoid found in fruits and vegetables that has been reported to be mutagenic in vitro, but not necessarily carcinogenic to humans: [1, 2, 3]
In vitro
Quercetin is mutagenic in the Ames test and in other in vitro assays. However, quercetin's mutagenic activity can be significantly increased by microsomal activation. [1, 2, 3, 4]
In vivo
Some in vivo studies have reported that quercetin is carcinogenic in rats, but the results were not consistent and the methods used were unusual. Most in vivo studies indicate that quercetin is not carcinogenic. The International Agency for Research on Cancer (IARC) concluded in 1999 that quercetin is not classified as carcinogenic to humans. [3]
Safety
Quercetin is generally considered safe, and supplements are commercially available in the U.S. and Europe. Side effects may include headache and upset stomach, and very high doses may damage the kidneys. [3, 5]
Quercetin's mutagenicity can be inactivated by oxygen, oxidizing enzymes, and alkaline pH. [6]
Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. (2013)
The study by Spindler et al. (2013) investigated the effects of various fruit, leaf, spice, and seed phytonutrient extracts and isolated phytonutrients on the longevity of mice. The phytonutrients tested included blueberry extract, pomegranate extract, green tea extract, black tea extract, cinnamon extract, curcumin, morin, sesame extract (sesamin), Pycnogenol (maritime pine bark extract), quercetin, and taxifolin.
The study used male B6C3F1 mice, which are a robust, long-lived F1 hybrid strain. Treatment with the phytonutrient extracts or compounds began at 12 months of age. The mice were fed a controlled daily amount of food (13.3 kcal/day/mouse) containing the supplements or a control diet. Food consumption and body weight were measured throughout the study.
The key findings were:
None of the tested phytonutrient extracts or isolated compounds significantly increased the lifespan of the mice compared to control diet, based on Kaplan-Meier survival analysis.
In contrast, calorie restriction (CR) by 40% did significantly extend median and maximum lifespan of mice by 23% (p < 0.001), confirming the mice were responsive to life-extending interventions.
Most supplements did not affect body weight or food intake relative to control diet, indicating no major effect on energy absorption or utilization.
Green tea + black tea + morin lowered body weight despite matched calorie intake, possibly by increasing metabolism or locomotion.
Quercetin + taxifolin + Pycnogenol increased body weight compared to control, suggesting enhanced energy absorption.
The doses used for each compound were based on published studies showing efficacy for health benefits in mice.
A literature review of flavonoids and lifespan in model organisms (2016)
Quercetin, rutin, and their combinations modulate penile phosphodiesterase-5′, arginase, acetylcholinesterase, and angiotensin-I-converting enzyme activities: a comparative study (2018)
This study demonstrates the effects of rutin and quercetin and their various combinations on phosphodiesterase-5 (PDE-5), arginase, acetylcholinesterase (AChE), and angiotensin-I-converting enzyme (ACE) activities in vitro. The effects of the flavonoids against Fe2+- and sodium nitroprusside (SNP)-induced lipid peroxidation in rats’ corpus cavernosum tissues were also investigated. Quercetin and rutin were dissolved in dimethylsulfoxide (DMSO) to a final concentration of 1 mM each. Thereafter, their combinations (50% quercetin + 50% rutin [Q1:R1]; 75% quercetin + 25% rutin [Q3:R1]; 25% quercetin + 75% rutin [Q1:R3]) were prepared. Our findings revealed that both flavonoids inhibited PDE-5, arginase, AChE, and ACE activities. Rutin exhibited significantly higher inhibitory effects on PDE-5, AChE, and ACE activities compared to quercetin. Considering the combinations, Q1:R3 was more potent compared to Q1:R1 and Q3:R1. Both flavonoids inhibited Fe2+- and SNP-induced lipid peroxidation in rat’s corpus cavernosa tissues. Rutin also showed higher inhibitory effects on Fe- and SNP-induced lipid peroxidation. Similarly, the combinatorial effects of the flavonoids revealed that Q1:R3 significantly inhibited malondialdehyde (MDA) production compared to Q1:R1 and Q3:R1. In conclusion, our findings suggest that the combination of quercetin and rutin is more potent than their individual effect.
Sodium rutin extends lifespan and health span in mice including positive impacts on liver health (2022)
Background and purpose: Ageing is associated with progressive metabolic dysregulation. Rutin is a metabolic regulator with a poor solubility. Using soluble sodium rutin we investigating the effect and mechanisms of rutin in ageing process.
Experimental approach: Wild type male mice were treated with or without sodium rutin ( 0.2 mg·ml-1 in drinking water from 8-month-old until end of life. Kaplan-Meier survival curve was used for lifespan assay, ageing-related histopathology analysis and metabolic analysis were performed to determine the effects of chronic sodium rutin on the longevity. Serological test, liver tissue metabolomics and transcriptomics were used for liver function assay. SiRNA knockdown Angptl8 and autophagy flux assay in HepG2 cell lines explored the mechanism through which sodium rutin might impact the function of hepatocyte.
Key results: Sodium rutin treatment extends the lifespan of mice by 10%. Sodium rutin supplementation alleviates ageing-related pathological changes and promotes behaviour performance in ageing mice. Sodium rutin supplementation altered the whole-body metabolism in mice, which exhibited increased energy expenditure and lower respiratory quotient. Transcriptomics analysis showed that Sodium rutin affected the expression of metabolic genes. Metabolomics analysis showed that Sodium rutin reduced liver steatosis through increased lipid β-oxidation. Sodium rutin treatment increased the autophagy level both in vivo and in vitro. The inhibition of autophagy partially abolished the sodium rutin-mediated effect on lipolysis in HepG2 cells.
Conclusion and implications: Sodium rutin treatment extends the lifespan and health span of mice with beneficial effects on metabolism, which were achieved by enhancing the autophagy activity in hepatocytes.
Anti-aging Effect of Rutin in Caenorhabditis elegans and D-Gal-Induced Aging Mouse Model
Caenorhabditis elegans and D-Gal-induced aging mouse model were used to investigate the anti-aging effect of rutin. The effects of different concentrations of rutin (0, 12.5, 25, and 50 μg/mL) on locomotor behavior, reproductive rate, and lifespan of C. elegans were determined. For establishing the aging mouse model, D-Gal (200 mg/kg) was subcutaneously injected into the back of mice, and mice were treated with rutin (200 mg/kg). At the end of treatment, memory and motor function was assessed by nest building test, open field test, and Y-maze. Serum and brain tissue were collected from each mouse to examine the ROS, lipofuscin, MDA, GSH-Px, and SOD levels. The results showed that rutin prolonged the lifespan of C. elegans, and increased the number of eggs of C. elegans (p < 0.05). In addition, rutin significantly improved the exercise capacity in mice (p < 0.05) and significantly reduced brain tissue ROS (p < 0.05) and MDA (p < 0.01) levels. Meanwhile, rutin could enhance the activity of SOD (p < 0.05) and GSH-Px (p < 0.01) significantly in the serum and brain. In summary, rutin exhibits anti-senescence capabilities which could be ascribed to its antioxidant activities.
Quercetin (link)
Quercetin is a dietary flavonoid found in fruits, vegetables, teas, and medicinal plants. It has antioxidant, anti-inflammatory, and potential anticancer effects in lab studies (Lamson and Brignall, 2000). However, clinical trials in humans are limited and results are mixed (Janssen et al., 1998; Beatty et al., 2000).
Lab studies show quercetin has antioxidant effects due to its ability to neutralize free radicals (Lamson and Brignall, 2000). It may also have anti-inflammatory effects by inhibiting release of histamine and other inflammatory mediators (Askari et al., 2012).
Numerous lab studies show potential anticancer effects of quercetin against various cancer cell types (Sharmila et al., 2013). However, systematic review found it does not reduce ovarian cancer risk (Parvaresh et al., 2016). Quercetin was also found to increase growth of estrogen-receptor positive breast cancer in a mouse model (Singh et al., 2010).
One small study found quercetin with red wine extract lowered LDL oxidation in healthy volunteers (Chopra et al., 2000). However, effect of quercetin alone is unclear. Overall, evidence for cardioprotective effects in humans is limited.
Quercetin supplementation showed mixed results on exercise performance and recovery in small trials - some found reduced muscle damage and enhanced performance (Bazzucchi et al., 2019), while others found no effect (Brüll et al., 2017).
In patients with rheumatoid arthritis, quercetin improved symptoms and disease activity compared to placebo in one small trial (Javadi et al., 2017).
Quercetin may interact with cytochrome P450 3A4 substrate medications (Sergent et al., 2009). It increased systemic exposure of losartan in animal model (Zhao et al., 2019). Overall, herb-drug interaction data in humans is limited.
Typical dietary quercetin intake provides low bioavailability. High dose supplements may provide greater circulating levels (Erlund et al., 2000). However, optimal dosing for potential therapeutic effects is unknown.
Overall, while quercetin shows promising effects in lab and animal studies, there is currently limited clinical trial data to support its use to treat specific conditions in humans. More large, high-quality clinical trials are needed.
Quercetin (link)
Quercetin is a flavonoid antioxidant found in many fruits, vegetables, teas, and wines. Flavonoids like quercetin scavenge free radicals and may help prevent some of the damage caused by oxidative stress (Boots et al 2008). In vitro studies show quercetin has strong antioxidant properties, but it is unclear if oral supplementation has the same effects in humans (Boots et al 2007).
Potential benefits of quercetin:
Allergies: Quercetin prevents immune cells from releasing histamines in test tubes. Researchers hypothesize it may reduce allergy symptoms like runny nose, watery eyes, hives, and swelling, but human evidence is currently lacking (Hanninen et al 2000, Thornhill et al 2000).
Heart health: Population studies link higher flavonoid intake to lower cardiovascular disease risk. Quercetin may help prevent atherosclerosis by protecting against LDL cholesterol damage. However, human studies are limited and use higher doses than supplements provide (Egert et al 2009, Edwards et al 2007, Knekt et al 2000).
Cholesterol: Test tube and population research associates quercetin with lower LDL cholesterol. Small RCTs show quercetin supplements reduce LDL cholesterol in at-risk and overweight subjects (Dower et al 2014, Egert et al 2009).
Hypertension: Quercetin supplementation significantly reduces blood pressure in hypertensive patients according to some studies (Edwards et al 2007, Mackraj et al 2008).
Prostatitis: One small RCT observed fewer prostatitis symptoms in men taking quercetin vs placebo, but more research is needed (Shoskes et al 2011).
Cancer: Population studies link higher dietary flavonoid intake to lower cancer risk. In vitro and animal research shows quercetin inhibits growth of breast, colon, prostate, ovarian, endometrial, and lung cancer cells. However, human evidence is limited (Lamson et al 2000, Maso et al 2014).
Quercetin may also have anti-inflammatory and antihistamine properties (Boots et al 2008, Hanninen et al 2000).
Key statistics:
Hypertension: 500 mg/day quercetin for 4 weeks reduced systolic blood pressure by -7 ± 2 mm Hg compared to placebo in a randomized, double-blind, placebo-controlled, crossover trial in 22 subjects (p<0.01) (Edwards et al 2007).
LDL cholesterol: 150 mg/day quercetin for 6 weeks significantly reduced LDL cholesterol by -0.45 ± 0.11 mmol/L compared to placebo in a randomized, double-blind, placebo-controlled, crossover trial in 93 overweight subjects (p<0.001) (Egert et al 2009).
Safety: Doses above 1000 mg/day may damage the kidneys. Quercetin is likely safe at typical supplemental doses (Harwood et al 2007).
Bioavailability: Quercetin has relatively low bioavailability. Combining quercetin with bromelain, vitamin C, or lipids may increase absorption (Rakel 2012).
Quercetin (heathline)
What is quercetin?
Quercetin is a pigment that belongs to a group of plant compounds called flavonoids. It is one of the most abundant flavonoids in the human diet.
Good dietary sources of quercetin include onions, apples, grapes, berries, broccoli, cherries, citrus fruits, green tea, red wine and capers. It is also available as a dietary supplement.
Quercetin acts as an antioxidant in the body, helping to combat free radical damage that is linked to chronic disease development.
Inflammation reduction:
In cell studies, quercetin reduced inflammatory markers like TNF-alpha and IL-6.
An 8-week study in women with rheumatoid arthritis found that 500mg/day of quercetin significantly reduced morning pain, stiffness and inflammatory markers compared to placebo (Javadi et al, 2016).
More human research is needed, but current evidence suggests quercetin may help reduce inflammation.
Allergy symptom relief:
Quercetin may block enzymes and chemicals involved in inflammation and allergic responses.
Animal studies show quercetin supplements prevented peanut-induced anaphylactic reactions, suggesting a potential anti-allergy effect (Shishehbor et al, 2010).
More studies in humans are required to confirm if quercetin can provide allergy relief.
Anticancer effects:
As an antioxidant, quercetin may have anti-cancer properties.
Test tube and animal studies show it suppressed growth and induced death of various cancer cells, including prostate, liver, lung and colon (Yang et al, 2015; Hashemzaei et al, 2017).
Human research is lacking, so the anticancer effects are currently speculative.
Brain health:
Quercetin's antioxidant properties may help protect the brain from disorders like Alzheimer's and dementia.
Animal studies found quercetin reversed Alzheimer's disease markers and improved cognitive function in mice with the disease (Sabogal-Guáqueta et al, 2015).
The primary compound in coffee linked to reduced Alzheimer's risk is believed to be quercetin, not caffeine (Lee et al, 2016).
More human studies are needed to confirm the brain health benefits.
Blood pressure reduction:
Quercetin appears to have a relaxing effect on blood vessels.
Animal studies show quercetin supplementation reduced systolic and diastolic blood pressure (Duarte et al, 2001).
A review of 9 human studies found that >500mg/day of quercetin reduced systolic and diastolic blood pressure (Serban et al, 2016).
More research is required, but quercetin may aid blood pressure management.
Other potential benefits:
May help combat aging by eliminating aging cells (Sohn et al, 2018).
May slightly improve exercise endurance performance (Kressler et al, 2011).
May help control blood sugar levels and protect against diabetes complications based on preliminary evidence (Shi et al, 2019).
Food sources and supplements:
Quercetin intakes from food are estimated at 10–100 mg per day for the average person.
Rich food sources include onions, apples, grapes, cherries, citrus fruits, broccoli, berries, green tea and red wine.
Quercetin supplements are available in doses around 500–1000 mg per day. Absorption may be enhanced by pairing with vitamin C, bromelain or other flavonoids.
Safety and side effects:
Quercetin from foods is considered safe. Supplements also appear relatively safe at recommended dosages, with minimal side effects.
Mild side effects like headaches or tingling may occur at doses over 1000 mg per day (Andres et al, 2017).
Quercetin may interact with some medications, so consult a doctor before supplementing.
Safety for pregnant or breastfeeding women is uncertain, so quercetin supplementation is not recommended.
Key conclusions:
Quercetin is a naturally occurring flavonoid antioxidant found in plant foods like onions, apples, tea and red wine.
It may help combat inflammation, allergies, cancer, high blood pressure and other conditions, but more human research is needed.
Quercetin from foods is safe, while supplements appear relatively safe at recommended dosages under 1,000 mg per day.
Quercetin shows promise as a supplement, but human studies are currently limited. Consulting a doctor before use is recommended.
Quercetin (link)
Quercetin is a flavonol, a type of flavonoid antioxidant found in many fruits, vegetables, herbs and nuts. Several potential health benefits of quercetin:
Antioxidant effects
Quercetin is a more powerful antioxidant than vitamin C, vitamin E or beta carotene (Ozgen et al, 2016).
Its antioxidant properties may help fight free radicals, which are unstable molecules that can damage cells and contribute to disease and aging (Selamoglu, 2016).
Anti-inflammatory effects
Quercetin may help inhibit inflammation in the body (Saeedi-Boroujeni et al, 2021).
However, it's unclear if high-dose quercetin supplements benefit inflammation in humans.
Anticancer effects
Diets high in flavonoid-rich fruits and vegetables are associated with reduced cancer risk, but more research is needed on quercetin specifically (Rather et al, 2019).
Neuroprotective effects
Quercetin may help protect against neurodegenerative diseases like Alzheimer's. This may be related to its antioxidant effects (Zhang et al, 2020).
24 weeks of quercetin-rich onion intake reduced age-related cognitive decline in one human study (Nishihira et al, 2021).
Allergy symptom relief
Quercetin may act as a natural antihistamine and restrict histamine release (David et al, 2016).
However, more studies in humans are needed, especially for quercetin supplementation.
Antimicrobial effects
Quercetin has antibacterial and antiviral properties in lab studies (Yang et al, 2020; De Patrillo et al, 2021).
It may help inhibit the growth of bacteria like Salmonella, Staphylococcus aureus, and E. coli.
Heart health
Diets rich in flavonoids are associated with reduced heart disease risk. Quercetin may help protect heart health by improving blood vessel function (Dagher et al, 2021).
Lowering blood pressure
A meta-analysis found quercetin supplementation significantly reduced blood pressure (Tamtaji et al, 2019).
150 mg/day of quercetin lowered LDL cholesterol and systolic blood pressure in overweight adults (Egert et al, 2010).
In summary, quercetin is a dietary flavonoid with antioxidant, anti-inflammatory and antimicrobial properties that may promote health. However, human research is limited, and optimal dosing requires more study.
Quercetin (wikipedia)
Quercetin is a flavonoid compound found abundantly in fruits, vegetables, grains, seeds, leaves and other plant foods. It has a bitter flavor and is used as a dietary supplement ingredient and food additive.
Occurrence:
Quercetin is one of the most abundant flavonoids in the human diet, with average daily intake of 25-50 mg.
Foods highest in quercetin include capers (234 mg/100g), lovage leaves (170 mg/100g), sorrel (86 mg/100g), radish leaves (70 mg/100g), and many common fruits and vegetables (3-50 mg/100g range).
Red onions contain more quercetin in the outermost rings and near the root (32 mg/100g) (Slimestad et al., 2007).
Organically grown tomatoes have been found to contain 79% more quercetin than conventionally grown tomatoes (Mitchell et al., 2007).
Quercetin is also present in various honeys from different plant sources (Petrus et al., 2011).
Biosynthesis:
In plants, quercetin is synthesized from the amino acid phenylalanine through the phenylpropanoid pathway and flavonoid biosynthesis pathway (Winkel-Shirley, 2001).
Glycosides:
Quercetin occurs naturally as glycosides, attached to various sugar moieties such as glucose, galactose, rhamnose, among others.
Common quercetin glycosides include rutin, quercitrin, isoquercitrin, hyperoside and quercetin-3-O-glucoside.
Pharmacokinetics:
Bioavailability of quercetin in humans is very low when consumed orally (<1%), due to rapid and extensive metabolism (Gugler et al., 1975; Graefe et al., 1999).
Intravenous injection shows a rapid distribution half-life of 8.8 minutes and elimination half-life of 2.4 hours (Gugler et al., 1975).
Co-ingestion with dietary fats or carbohydrates may increase bioavailability (Dabeek & Marra, 2019).
Metabolism:
Quercetin undergoes extensive phase II metabolism into glucuronidated, sulfated and methylated metabolites (Wittig et al., 2001; Day et al., 2004).
Major plasma metabolites in humans are quercetin-3-glucuronide, 3′-methylquercetin-3-glucuronide and quercetin-3′-sulfate (Wittig et al., 2001).
It is a strong in vitro inhibitor of CYP3A4 and CYP2C19, and a moderate inhibitor of CYP2D6, which may affect metabolism of drugs broken down by these pathways (Elbarbry et al., 2018; Rastogi & Jana, 2014).
Mechanism of Action:
Displays antioxidant activity in vitro by scavenging free radicals (Williams et al., 2004).
May inhibit activity of various kinases and pathways linked to cancer, apoptosis and inflammation (Yang et al., 2015).
However, in vivo relevance is unclear due to extensive metabolism.
Pharmacological Effects:
Small clinical trials and animal research suggest potential benefits for cancer, cardiovascular health, immunity, diabetes, cognition and more. However, high quality evidence from human trials is lacking (Gross, 2009; Miles et al., 2014; D’Andrea, 2015).
Safety and Regulation:
Considered safe as a food additive at levels up to 500 mg/serving by the U.S. FDA (2010).
Little research on safety of quercetin supplements. Possible concerns include hormone effects and drug interactions (Andres et al., 2018).
Health claims for disease treatment are not permitted, but structure/function claims may be allowed (King, 2017).
In summary, quercetin is an abundant dietary flavonoid found in many plant foods that displays antioxidant and anti-inflammatory activities in vitro. Its bioavailability from oral intake is very low but may be enhanced by certain food matrices. While preclinical evidence suggests it may benefit several diseases, high quality data from human clinical trials is currently insufficient to support its use as a supplement for disease prevention or treatment. Safety of chronic, high-dose quercetin supplementation remains uncertain. Additional rigorous research is needed to better understand its pharmacological potential and safety profile in humans.
Quercetin (very well)
The article provides an overview of the flavonoid quercetin, its potential health benefits, food sources, side effects, precautions for use, dosage, toxicity, interactions, and what to look for in supplements. Some key conclusions, points, and results include:
Quercetin is a plant pigment and flavonoid found naturally in many foods like apples, onions, teas, berries, red wine, and herbs. It has antioxidant and potential anti-inflammatory properties but currently lacks sufficient evidence from human studies to support its use for any specific health condition.
Purported uses of quercetin based on preliminary research include benefits for heart disease, cancer, arthritis, bladder infections, allergies, and COVID-19. However, there is insufficient evidence from human studies to recommend quercetin supplementation for these conditions.
A meta-analysis of 7 trials with 587 participants found that quercetin supplementation significantly reduced systolic and diastolic blood pressure compared to placebo, especially at doses of 500mg/day or higher. However, the clinical significance is uncertain and more research is needed (Serban et al., 2016).
A small study of 50 women with rheumatoid arthritis found that 500mg/day of quercetin for 8 weeks significantly reduced morning stiffness, morning pain, after-activity pain, and markers of inflammation compared to placebo. This indicates a potential anti-inflammatory effect but larger studies are required (Javadi et al., 2017).
Quercetin is generally well tolerated at appropriate doses (250-1000mg) for short term use (up to 12 weeks) but can cause side effects like tingling, upset stomach, and headaches at high doses. It should be avoided in pregnancy, lactation, children, and kidney disease.
Quercetin may interact with many medications including blood pressure drugs, diabetes drugs, antibiotics, immune suppressants, anticoagulants, and antidepressants. It may also interact with other supplements.
Food sources of quercetin include onions, apples, teas, buckwheat, citrus fruits, cherries, berries, and red grapes. Supplements often combine quercetin with bromelain and papain to increase absorption.
When choosing a quercetin supplement, select products tested by third parties like USP, ConsumerLabs, or NSF. However, safety and efficacy are not guaranteed. Supplements are not regulated by FDA like prescription medications.
There is insufficient evidence from human studies to recommend quercetin supplementation for any specific health condition. While generally safe at appropriate doses short-term, it has many potential medication and supplement interactions. Those interested in quercetin supplementation should consult a healthcare professional.
More large, high-quality human trials are needed to establish quercetin's efficacy and safety for various health conditions. Current evidence is preliminary but indicates it may have anti-inflammatory effects and help lower blood pressure, though clinical significance remains unclear.
In summary, the article provides an overview of quercetin and concludes there is insufficient evidence to support its use for any health purpose currently. Preliminary research shows potential anti-inflammatory and blood pressure lowering effects but clinical relevance is uncertain. Those interested in taking quercetin supplements should consult a healthcare provider due to many possible medication and supplement interactions. More research is warranted to establish quercetin's efficacy and safety profile.
Effects of Quercetin on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Background
Quercetin, the most abundant dietary flavonol, has antioxidant effects in cardiovascular disease, but the evidence regarding its effects on blood pressure (BP) has not been conclusive. We assessed the impact of quercetin on BP through a systematic review and meta-analysis of available randomized controlled trials.
Methods and Results
We searched PUBMED, Cochrane Library, Scopus, and EMBASE up to January 31, 2015 to identify placebo-controlled randomized controlled trials investigating the effect of quercetin on BP. Meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Effect size was expressed as weighted mean difference (WMD) and 95% CI. Overall, the impact of quercetin on BP was reported in 7 trials comprising 9 treatment arms (587 patients). The results of the meta-analysis showed significant reductions both in systolic BP (WMD: −3.04 mm Hg, 95% CI: −5.75, −0.33, P=0.028) and diastolic BP (WMD: −2.63 mm Hg, 95% CI: −3.26, −2.01, P<0.001) following supplementation with quercetin. When the studies were categorized according to the quercetin dose, there was a significant systolic BP and diastolic BP-reducing effect in randomized controlled trials with doses ≥500 mg/day (WMD: −4.45 mm Hg, 95% CI: −7.70, −1.21, P=0.007 and −2.98 mm Hg, 95% CI: −3.64, −2.31, P<0.001, respectively), and lack of a significant effect for doses <500 mg/day (WMD: −1.59 mm Hg, 95% CI: −4.44, 1.25, P=0.273 and −0.24 mm Hg, 95% CI: −2.00, 1.52, P=0.788, respectively), but indirect comparison tests failed to significant differences between doses.
Anticancer and apoptosis inducing effects of quercetin in vitro and in vivo
The anticancer activity of quercetin at 10, 20, 40, 80 and 120 µM was assessed in vitro by MMT assay in 9 tumor cell lines (colon carcinoma CT-26 cells, prostate adenocarcinoma LNCaP cells, human prostate PC3 cells, pheocromocytoma PC12 cells, estrogen receptor-positive breast cancer MCF-7 cells, acute lymphoblastic leukemia MOLT-4 T-cells, human myeloma U266B1 cells, human lymphoid Raji cells and ovarian cancer CHO cells). Quercetin was found to induce the apoptosis of all the tested cancer cell lines at the utilized concentrations. Moreover, quercetin significantly induced the apoptosis of the CT-26, LNCaP, MOLT-4 and Raji cell lines, as compared to control group (P<0.001), as demonstrated by Annexin V/PI staining. In in vivo experiments, mice bearing MCF-7 and CT-26 tumors exhibited a significant reduction in tumor volume in the quercetin-treated group as compared to the control group (P<0.001). Taken together, quercetin, a naturally occurring compound, exhibits anticancer properties both in vivo and in vitro.
Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells
These results demonstrate that curcumin and quercetin inhibit cancer cell proliferation synergistically and Wnt/β-catenin signaling and apoptotic pathways are partly responsible for antiproliferative activities.
Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-Line Sunitinib (QUASAR): Results of a Phase I Trial
Isoquercetin given concomitantly with sunitinib reduced fatigue and adverse events. GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). Isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.
Quercetin Inhibits Fibroblast Activation and Kidney Fibrosis Involving the Suppression of Mammalian Target of Rapamycin and β-catenin Signaling
Quercetin inhibits fibroblast activation and kidney fibrosis involving a combined inhibition of mTOR and β-catenin signaling transduction, which may act as a therapeutic candidate for patients with chronic kidney diseases.
Combination of quercetin and hyperoside has anticancer effects on renal cancer cells through inhibition of oncogenic microRNA-27a
Synergistic effects of snail and Quercetin on Renal Cell Carcinoma Caki-2 by altering AKT/mTOR/ERK1/2 signaling pathways
Meng et al. (2015) combined quercetin with anti-sense oligo gene therapy (Snail gene inhibition) and found that each suppressed the proliferation and migration of Caki-2 cells, inducing cell cycle arrest and apoptosis, with a strong suppression of renal carcinoma cells being achieved by their combination.
Quercetin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and activation of JAK2/STAT3 pathway: A target based networking pharmacology approach (2022)
Senolytics improve physical function and increase lifespan in old age
Transfer of senescent cells into naive, young mice can induce physical dysfunction, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice. Quercetin has been found to alleviate a variety of disorders through diverse mechanisms of action, almost all of which have been studied with uninterrupted dosing, resulting in quercetin being continuously present. This is consistent with the presumption that quercetin acts on specific enzymes or pathways to achieve these effects. However, in our study, we administered D + Q intermittently. Dasatinib and quercetin both have short elimination half-lives, supporting the possibility that their beneficial effects on late-life function and survival were at least partially due to a mechanism that persists long after the drugs are no longer present, such as senescent cell elimination. Dasatinib can have side effects, occasionally including serious ones such as pulmonary edema, which can occur after 8–48 months of daily administration. Although recognized side effects of drugs in mice often differ substantially from those in humans, in our study, mice given D + Q intermittently lived longer and had improved physical function compared to vehicle-treated mice.
intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%.
Biology of Quercetin
Flavonoid compounds, such as quercetin, were initially studied for their biological activity in affecting capillary wall resistance (19) and continue to be investigated for their effects on vascular tension (20). Dietary supplements differ, but often contain the free form of quercetin—quercetin aglycone—under the FDA national drug code numbers 65448-3085, 65448-3005 (21). Once consumed, quercetin passes predominantly unaltered into the large intestine (22). Quercetin acts as a free radical scavenger, donating two electrons via o-quinone/quinone methide (23); both in vitro and in vivo (24, 25) studies implicate quercetin as a potent antioxidant. This antioxidant activity may also be potentiated by vitamin C (26), as will be discussed below. There is also significant longstanding interest in the anti-inflammatory activity of quercetin, as it has been suggested to be a key mediator in the cardiovascular protective element of the “Mediterranean” diet (27). This biological rationale is secondary to quercetin's free radical scavenging capacity, alongside diverse roles identified in in vitro and in vivo models including: inhibition of platelet aggregation (28), inhibition of lipid peroxidation (29), and its inhibitory effects on pro-inflammatory mediators such as lipoxygenase (30) and phospholipase A2 (31). This anti-inflammatory effect is primarily mediated by flavonoid activity on arachidonic acid metabolism and the associated leukotriene/prostaglandin pathways. Furthermore, 3-methyl-quercetin, a quercetin metabolite, displays stimulatory effects on nasal epithelial cell ciliary beat frequency, both in vitro and in vivo, when administered either alone or with absorption enhancer HP-β-CD (32). Quercetin also affects the function of several lipids, protein tyrosine, and serine/threonine kinases (33, 34), such as phosphatidylinositol (PI)-3-kinase and inducible nitric oxide synthase (NOS2) (35, 36).
Beneficial Effects of Vitamin C and Quercetin in Viral Infections
There is a tremendous amount of literature supporting the antiviral properties of quercetin, in both in vitro and in vivo experiments. Quercetin inhibits several respiratory viruses in cultured cells (16, 37). It inhibits the cytopathic effects provoked by many serotypes of rhinovirus, echovirus (type 7, 11, 12, and 19), coxsackievirus (A21 and B1), and poliovirus (type 1 Sabin) at a minimal inhibitory concentration of 0.03 to 0.5 μg/ml in Hela or WI-38 cells (38). Quercetin also significantly reduces plaque formation by RNA and DNA viruses [Respiratory Syncytial Virus (RSV), Polio type 1, parainfluenza type 3, and Herpes Simplex Virus-1(HSV-1)] displaying anti-infective and anti-replicative properties (39). It inhibits the replication of cytomegalovirus (CMV) inoculated HeLa cells at a half inhibitory concentration (IC50) of 3.2 ± 0.8 μM and with a selectivity index (SI) of 22 (40). Dengue virus type 2 (DENV-2) replication in Vero cells is inhibited by quercetin at an IC50 of 35.7 μg/mL, causing a DENV-2 RNA reduction of 67%. This is attributed to quercetin's ability to either block virus entry or inhibit viral replication enzymes such as viral polymerases (41).
Effects of Quercetin Supplementation on Hematological Parameters in Non-Alcoholic Fatty Liver Disease: a Randomized, Double-Blind, Placebo-Controlled Pilot Study (2020)
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease which has become a public health concern. Since oxidative stress plays a crucial role in the pathogenesis of NAFLD, subsequent hematological disorders are expected. Therefore, antioxidant compounds such as quercetin could ameliorate the related side-effect of oxidative stress. The aim of the current study was to assess the effect of quercetin on hematological parameters in NAFLD patients. A randomized, double-blind, placebo-controlled trial was conducted as a pilot study. In this study 90 patients with NAFLD were supplemented with either a quercetin or a placebo capsule twice daily (500 mg) for 12 weeks. Blood sample was obtained for laboratory parameters at baseline and the end of week 12. End of trial values for red blood cell (RBC; p = 0.002), mean corpuscular hemoglobin concentration (p = 0.029), and mean platelet volume (p = 0.017), significantly increased and the levels of mean corpuscular volume (MCV; p = 0.023), RBC distribution width-coefficient of variation (p = 0.005), platelet distribution width (p = 0.015), and ferritin (p = 0.002) significantly decreased compared to the baseline in group receiving quercetin. Between group analysis revealed that RBC significantly increased (p = 0.025) but, mean corpuscular volume (p = 0.004), mean corpuscular hemoglobin (MCH; p = 0.002), and ferritin (p = 0.013) significantly decreased compared to placebo group. In this work quercetin showed significant effect on RBC, ferritin, MCV, and MCH in intervention group.
Nonalcoholic fatty liver disease: The role of quercetin and its therapeutic implications (2021)
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting almost one-third of the general population and 75% of obese patients with type 2 diabetes. The aim of this article is to review the current evidence concerning the role of quercetin, a natural compound and flavonoid, and its possible therapeutic effects on this modern-day disease. Despite the fact that the exact pathophysiological mechanisms through which quercetin has a hepatoprotective effect on NAFLD are still not fully elucidated, this review clearly demonstrates that this flavonoid has potent antioxidative stress action and inhibitory effects on hepatocyte apoptosis, inflammation, and generation of reactive oxygen species, factors which are linked to the development of the disease. NAFLD is closely associated with increased dietary fat consumption, especially in Western countries. The hepatoprotective effect of quercetin against NAFLD merits serious consideration and further validation by future studies.
Clinical effectiveness of quercetin supplementation in the management of weight loss: a pooled analysis of randomized controlled trials (2019)
Purpose:
The previous investigations which considered the possible effect of the quercetin supplementation for overweight and obesity have led to inconsistent results. Here, we aimed to evaluate the effects of quercetin on weight loss using a meta-analysis of randomized controlled clinical trials (RCTs).
Methods:
Relevant studies were systematically searched from the MEDLINE, EMBASE, Google Scholar, and Scopus databases. RCTs that investigated the effects of quercetin on weight loss in humans were included for quality assessment, meta-analyses, sensitivity analysis, subgroup analyses, and publication bias assessment. Effect size was expressed as weighted mean difference (WMD) and 95% CI by using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to rate the level of evidence.
Results:
Nine RCTs (11 treatment arms) with 525 participants were finally included for data pooling. Our meta-analysis revealed that daily quercetin supplementation did not significantly affect the body weight (WMD: −0.35 kg, 95% CI: −2.03, 1.33; P=0.68), body mass index (WMD: −0.04 kg/m2, 95% CI: −0.54, 0.45; P=0.87), waist circumference (WMD: −0.37 cm, 95% CI: −1.81, 1.06; P=0.61), and waist to hip ratio (WMD: −0.01, 95% CI: −0.03, 0.01; P=0.48). Subgroup analysis could not identify factors significantly influencing these parameters. These results were robust in sensitivity analysis, and no significant publication bias was found.
Conclusion:
The current evidence suggests that quercetin intake did not show a notably favorable effect on weight loss. Future well-designed and long-term clinical trials are required to confirm these results.
Latest Research on Natural JAK2 Inhibitors
Two recent papers scanned natural molecules to identify what could be the most powerful natural JAK2 inhibitors. This research was through computer simulations, not via cell, mice or human studies. So its results cannot be taken as definitive. But the results were fairly interesting. I'll highlight four of many molecules identified.
Chlorogenic acid: Found abundantly in coffee and tomatoes. You can incorporate this to your diet via regular coffee consumption (lighter roasts have higher amounts of chlorogenic acid). Low Sodium Vegetable Juice (V8) can also be a great addition to complement a mediterrenean diet. I'm doing both.
Rutin: I've taken 100mg Rutin as part of Wobenzym for the past 1 yr. It's very effective for increasing energy. This supplement increases depression (like interferon therapy). So you have to be careful about it -- reduce or skip the dose, if you feel negative mood coming. But it's very effective for reducing MPN symptoms such as fatigue in my experience.
Quercetin: Has many many publications demonstrating JAK2 inhibition across many cell lines and mice studies. The most recent research suggests you get JAK2 inhibition at practically relevant dosages [1]. So it might actually be very helpful for MPN symptoms. I have recently ordered it as a supplement.
Orientin / Vitexin. These molecules were identified to be the strongest JAK2 inhibiting compounds per molecule. They can be obtained via Rooibos tea which is a popular drink in some African countries. Orientin is very quickly eliminated from human body (1-2 hr half life). I ordered some Rooibos tea (2g/serving, 4.5mg Orientin) just to check it out, but I'm more hopeful about something like Quercetin 250mg which has 10-12hr half life in human body, and is available as a much higher dose supplement.
While we cannot expect any of the natural substances to stop or slow down JAK2V617F specifically, they might have benefits in symptom management by mildly slowing down JAK2 broadly.
[1] Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients (2024) https://onlinelibrary.wiley.com/doi/abs/10.1155/2024/1114928
[2] Molecular docking analysis of human JAK2 with compounds from tomatoes (2020) https://pmc.ncbi.nlm.nih.gov/articles/PMC8503773/
[3] TGF-Beta / Wobenzym. https://mylongevityjourney.blogspot.com/2023/04/tgf-beta-proteolytic-enzymes.html
[4] Coffee / Chlorogenic acid. https://mylongevityjourney.blogspot.com/2022/02/coffee-green-coffee-bean-extract.html
[5] Quercetin. https://mylongevityjourney.blogspot.com/2024/12/quercetin.html
Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice (Ruiz-2015)
Quercetin, a dietary flavonoid used as a food supplement, showed powerful antioxidant effects in different cellular models. However, recent in vitro and in vivo studies in mammals have suggested a prooxidant effect of quercetin and described an interaction with mitochondria causing an increase in O2 ∙− production, a decrease in ATP levels, and impairment of respiratory chain in liver tissue. Therefore, because of its dual actions, we studied the effect of quercetin in vivo to analyze heart mitochondrial function and erythropoiesis. Mice were injected with 50 mg/kg of quercetin for 15 days. Treatment with quercetin decreased body weight, serum insulin, and ceruloplasmin levels as compared with untreated mice. Along with an impaired antioxidant capacity in plasma, quercetin-treated mice showed a significant delay on erythropoiesis progression. Heart mitochondrial function was also impaired displaying more protein oxidation and less activity for IV, respectively, than no-treated mice. In addition, a significant reduction in the protein expression levels of Mitofusin 2 and Voltage-Dependent Anion Carrier was observed. All these results suggest that quercetin affects erythropoiesis and mitochondrial function and then its potential use as a dietary supplement should be reexamined.
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