• Leo Rex

Supplementing Quercetin for Neurotrophic and Senolytic Effects

Updated: Nov 3

Click here to watch the companion video to this blog post.


My favorite quercetin supplements:

  1. Thorne Research's Phytosomal Quercetin, which you can find here.

  2. Double Wood's very cheap product, which you can find here.

  3. BulkSupplements' product, which you can find here.

A comparison of these products' prices per mg of quercetin can be found at this end of this blog post.


FLAVONOIDS


1. Flavonoids are categorized into flavonols, flavones, flavanones, catechins, and anthocyanidins[1].

a. Flavonols include quercetin, fisetin, galangin, kaempferol, myricetin, quercitrin, and rutin.

2. Quercetin (3,3’,4’,5,7-pentahydroxylflavone) is the most prevalent flavonoid in food, followed by kaempferol[2].

3. Quercetin is found as quercetin aglycone in food and quercetin rutinoside (also called rutin) in tea, where aglycone is absorbed more quickly and uniformly by people[3].

4. The richest quercetin containing foods in descending order are elderberries, red onions, white onions, cranberries, green hot peppers, kale, blueberries, and red apples[4].


FREE RADICALS


1. Quercetin’s various metabolites have differential ability to scavenge free radicals[5][6].

2. Using human leukemia cells stimulated by lipopolysaccharides, quercetin was shown to inhibit reactive oxygen and nitrogen species with a higher reduction potential than curcumin at three different PHs and a total antioxidant capacity (TAC) 3.5x more powerful than curcumin[7].

3. On the DPPH assay, quercetin’s ability to scavenge free radicals is worse than EGCG and tied with epicatechin gallate (ECG), though it is superior to myricetin and kaempferol[8].

4. Quercetin’s ORAC score is lower than kaempferol and myricetin (and all of the catechins, which are led by epicatechin)[9].

5. In the FRAP and ABTS assays, quercetin is a better free radical scavenger than alpha-tocopherol[10].

6. It is less effective than epigallocatechin gallate (EGCG) at inhibiting DNA damage but more capable at producing DNA damage (at high concentrations)[11].


THE BRAIN


1. Nanoparticles have been developed to deliver quercetin[12][13].

2. Quercetin reduced oxidative stress by inhibiting inducible nitric oxide synthase protein expression and mitochondrial superoxide radicals and reduced the expression of IL-6, IL-1beta, and TNF-alpha in microglia treated with the Parkinsonian toxin MPP[14].

3. In rodent models of cerebral ischemia (hypoxic brain), quercetin protects neurons from apoptosis likely via upregulated of TrkB and BDNF[15].

4. Higher doses of quercetin increase BDNF mRNA in the rodent hippocampus[16].

5. In a model of polychlorinated biphenyl (PCBs) toxicity, PCB-induced suppression of rodent steroidogenesis was attenuated by quercetin. Quercetin also attenuated reductions on estrogen receptors in the hippocampus and BDNF signaling[17].

6. In a model of dimethylhydrazine-induced colorectal cancer, quercetin (with exercise) reduced tumor incidence, improved depressive symptoms, and upregulated BDNF[18].

7. In a model of lipopolysaccharide-induced rodent depression (and anxiety[19]), quercetin could attenuated LPS-induced downregulation of BDNF[20].

8. In a rodent model of oxidative injury to a mother, quercetin given to the mother improved BDNF signaling in offspring[21].

9. In rodents, quercetin can prophylactically protect rodents from memory impairments due to hypoxia[22].

10. In a rodent model of transgenic Parkinsonian mice, it appears that quercetin attenuates the progression of the disease[23].

11. Pre-treatment with quercetin limits dopaminergic neuron loss from the MPP toxin[24].

12. Quercetin improved BDNF expression after a spinal chord injury to rodents[25].

13. In a transgenic rodent model of Alzheimer’s, quercetin was more effective at attenuating the pathology of beta amyloid plaques when the rodents were given less vitamin D[26].

14. Quercetin’s neuroprotective element may require greater concentrations of the flavonoid than myricetin[27].

15. Chronic unpredicted stress (CUS) produces cognitive dysfunction and insulin resistance in rodents. Quercetin upregulates GLUT4 expression in the hippocampus and alleviates memory dysfunction[28].

16. Quercetin protects against dopaminergic dysfunction due to cadmium toxicity in a rodent model[29].

17. Quercetin and its glucosides (including rutin) affect alpha7 nicotinic cholinergic receptor ion currents. Quercetin increases them and rutin most potently decreases them[30].

18. Quercetin can attenuate GABA-A alpha5 receptor downregulation due to glutamate excitotoxicity (as seen here in a mouse seizure model with kainic acid[31]).


CANCER


1. Quercetin is selectively cytotoxic against cancers cells of blood, brain, lung, uterine, skin, and salivary glands[32].

a. It is compared to other flavonoids in this paper[33].

2. Quercetin aglycone interacts with the aryl hydrocarbon receptor and modulates MEK/ERK and Nrf2/keap1 pathways[34].

3. Quercetin is also thought to reduce the phosphorylation of activated heat shock protein transcription factor (HSF)[35], allowing it to experience proteolytic degradation, thereby reducing heat shock protein expression[36]. Heat shock proteins are overexpressed in tumors[37].

4. Quercetin inhibits breast cancer stem cell development[38].

5. Quercetin’s cytotoxicity to human prostate and skin cancer cell lines is enhanced with ultrasound use[39].

6. Quercetin sensitizes prostate cancer cells to chemotherapeutic medicines, such as docetaxel[40].

7. Quercetin improves apoptosis in human pancreatic cancer cell lines[41].

8. Quercetin suppresses the development of metastatic osteosarcoma cancer cells[42].

9. Quercetin nanoparticles exert an anti-tumor effect on hepatocellular carcinoma cells by inhibiting NFkB, COX-2, and Akt signalling[43].

a. Quercetin is also being investigated as a treatment for primary liver tumors (PLTs), due to its competitive inhibition of the glucose transporter 1 (GLUT1), which is upregulated in PLT[44].


THE LIVER


1. Quercetin upregulates the expression of metallothioneins, which in turn may phosphorylate JNK, p38, and PI3K/Akt, and may enhance Nrf2 activity. This produces a protective effect over hepatocytes[45].

2. In a rodent model of T2D-induced NAFLD, quercetin improved inflammatory measures, bile acid measures, and reduced fat retention in the liver[46].

3. Quercetin has improved measures of hepatic function in a rodent model of liver fibrosis[47].

4. Quercetin protects the liver from damage due to hyperthyroidism by upregulating the Nrf2 pathway[48].

5. Quercetin can protect the liver from damage due to T1D by inhibiting the CYP2E1 protein, as seen in a mouse model[49].

6. Quercetin protects rodents’ livers from ethanol-induced injury by inhibiting the Akt, NFkB, and STAT3 pathways[50].

7. In a rodent model of ethanol-induced liver steatosis, quercetin encouraged lipolysis in the liver and attenuated the inhibition of AMPK due to the chronic ethanol intake[51].

8. Quercetin is antifibrotic in rodents’ livers (tested with carbon tetrachloride[52]).

9. In a rodent model of lipopolysaccharide-induced liver injury, quercetin was hepatoprotective. It inhibited NFkB and MAPK signaling and limited hepatocyte apoptosis[53].

10. Quercetin aglycone appears more hepatoprotective than quercetin glucosides (the glycosylated forms)[54].

11. Liposomal nanoparticles of quercetin have also been used to protect rodent livers from acute injury[55].

12. The combination of fish oil and quercetin produced synergistic protection of rodent livers from oxidative stress due to Western diet[56].


THE KIDNEYS


1. Rutin, the quercetin glycoside, protected rodent kidneys from nephrotoxic effects of lipopolysaccharides[57].

2. Quercetin protects from acute kidney injury due to the chemotherapeutic drug, cisplatin[58].

3. Quercetin inhibits the iron-dependent necrosis of kidneys called ferroptosis[59].

4. Quercetin protects rodent kidneys from cadmium toxicity[60].

5. Quercetin combined with N-acetylglucosamine at a 1:1 ratio protected rodent kidneys from acute kidney injury synergistically[61].

6. In a rodent model of chronic kidney disease, quercetin appears to slightly improve kidney health metrics and reduce fibrosis[62].

7. In rodents with obstructive nephropathy, quercetin reduced fibrosis by suppressing mTORC1 and mTORC2[63].

8. It also reduces fibrosis by reducing renal tubular epithelial cell senescence[64] via SIRT1[65].


LUNGS


1. In a mouse model of lung fibrosis due to senescent idiopathic fibroblasts, quercetin attenuated pulmonary fibrosis[66].


FAT


1. In rodents, quercetin attenuated gains in bodyweight, as well as dyslipidemia, due to a high-fat diet in rodents by regulating the transcription of genes involved in lipogenesis[67].

2. At serum concentrations, quercetin can inhibit adipogenesis. At higher concentrations, it can reduce fat accumulation in mature adipocytes[68].

3. In combination with resveratrol, quercetin increases MUFA and PUFA levels, PPAR-alpha expression, and UCP2 expression in WAT[69].

4. In high-fat diet fed rodents, quercetin decreases inflammation in subcutaneous and visceral fat while red onion extract did so only for subcutaneous fat and instead increased inflammation in visceral fat. It also remodeled white adipose tissue and reduced circulation adipokines[70].

5. In rodents, quercetin appears to promote the browning of fat via activation of AMPK[71], or via the sympathetic nervous system, through which it upregulates both AMPK and PPAR-gamma, and, consequently, UCP1[72].


CARDIOVASCULAR HEALTH


1. In vitro, quercetin prevents the oxidation of LDL by macrophages, though it does this less effectively than fellow flavonoids morin and fisetin[73].

2. In rodents, quercetin attenuates left ventricular hypertrophy due to hypertension, likely by upregulating PPAR-gamma and downregulating AP-1 signaling[74].

3. In humans, quercetin supplementation (730 mg) reduced blood pressure only in hypertensives and despite a lack of improvement in markers of oxidative stress[75].

4. In rodents fed a methionine-rich diet, quercetin reduced homocysteine. It also elevated ALT and AST levels at higher doses[76].

5. Quercetin’s effect on hypertension and lipids varies significantly depending on whether people carry ApoE3 or ApoE4 genes[77].

a. Quercetin only decreased systolic blood pressure in ApoE3 carriers.

b. Quercetin worsened lipid ratios among ApoE4 carriers.

i. This is similar to how fish oil was observed to raise HDL levels in ApoE4 carriers[78].

6. Quercetin protects against myocardial ischemia-reperfusion injury by activating PPAR-gamma which in turn inhibits the NFkB pathway[79].


AGING


1. Quercetin supplementation prolonged the lifespans of C. elegans by 15%[80] due to the modulation of four genes and not caloric restriction/sirtuin effects[81].

2. Quercetin, to a lesser extent than resveratrol, is an indirect activator of SIRT1[82].

3. The major human quercetin metabolite quercetin-3-O-glucuronide weakly inhibits SIRT1 in human cell lines[83].

4. Supplementation with quercetin (0.1% of diets) significantly reduced the lifespans of mice[84].

5. Quercetin (in combination with the chemotherapeutic drug dasatinib) significantly decreased senescent cells in humans[85].


ESTROGEN


1. Quercetin can transactivate both alpha and beta estrogen receptors[86].

MICROBIOME


1. Quercetin can inhibit the growth of some bacteria[87].

2. Quercetin improves atherogenic metrics in rodents by modulating the microbiome and causing less synthesis of the atherogenic lysophosphatidylcholine[88].

3. Quercetin improves the diversity of the microbiome and attenuates disease pathology in a rodent model of colitis[89].

4. Quercetin attenuates dysbiosis due to antibiotics in rodents[90].


OTHER


1. Unlike the catechins, it appears that quercetin may stimulate melanin synthesis[91].

2. Quercetin may protect against the progression of arthritis[92]. 500 mg of quercetin taken daily improved the symptoms of arthritis in a controlled human study in Iran[93].

3. Quercetin binds to the vitamin D receptor and is consequently being studied as a first molecule on which to build an allosteric modulator of the vitamin D receptor[94].

4. There is evidence that quercetin may produce an antiviral outcome in upper respiratory tract infections[95].

5. Quercetin has been shown to improve symptoms of prostatitis in human trials[96].


SUPPLEMENTAL QUERCETIN


1. Safety of dietary supplementation with quercetin[97]:

a. Intakes of 3-40 mg of quercetin aglycone are common in Western diets, with hyperconsumers of fruits and vegetables consuming about 250 mg, while dietary supplements recommend 500-1000mg.

b. When metabolized, quercetin is mostly glucuronidated, sulfated, or methylated, though it may also be oxidized.

c. Quercetin is mostly found in the liver and kidneys, and to a lesser degree, in the brain, heart, and spleen.

d. Quercetin may worsen kidney function in those with impaired kidneys.

e. Quercetin has been shown to be mutagenic in smaller organisms (bacteria and yeast), possibly via its oxidation into o-quinone and quinone methide, though this was not shown in animal studies.

f. Chronic consumption of quercetin appears to decrease CYP1A2 and increase CYP2A6, CYP3A, and CYP3A5.

g. Quercetin can modulate steroidogenesis in some species and in some contexts (this has not been observed in humans).

h. It can alter the bioavailability of angiotensin receptor blockers, calcium channel blockers, PPAR agonists, statins, antipsychotics, and immunosuppressive drugs.

2. Bio-availability:

a. Quercetin Phytosome, a branded formulation of quercetin delivered with lecithin, is up to 20x more bioavailable[98].

b. Quercetin is better absorbed when taken with glucose[99].

c. Quercetin is more bioavailable when consumed with fats, and it is more bioavailable from onions than apples[100].

3. Questionable effectiveness:

a. In a randomized, double-blind, controlled trial of humans, quercetin supplementation (500 mg or 1000 mg) did not affect measures of oxidative stress[101].

b. Supplemental quercetin dose-dependently raises plasma quercetin levels but does not influence measures of oxidative stress[102].

4. Options:

a. Cheapest reviewed source: BulkSupplements.com is $0.11/500 mg of quercetin.

b. The least expensive tested capsule is Solaray Quercetin, which is $0.17/500 mg, though Double Wood’s contains bromelain and costs less than $0.07/500 mg.

c. Now brand is similarly cheap.

d. Thorne Research carries the Quercetin Phytosome which costs $.60/250 mg capsule made from sunflower lecithin.

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