Quercetin

Quercetin is a naturally occurring flavonoid found in a wide variety of fruits, vegetables, and grains. It is one of the most abundant antioxidants in the human diet and plays a significant role in helping to protect cells from damage caused by free radicals.

Quercetin belongs to the class of polyphenolic compounds known as flavonoids, recognized for their diverse biological activities. It is a pigment that is responsible, in part, for the colors of many fruits, vegetables, and flowers. Structurally, quercetin is characterized by the presence of a 15-carbon skeleton consisting of two phenyl rings and a heterocyclic ring.

The term "quercetin" is derived from quercetum (oak forest), reflecting its presence in oak trees. It was first isolated in 1857 by the Austrian chemist Heinrich Hlasiwetz. Since its discovery, quercetin has been the subject of extensive research, with numerous studies exploring its potential health benefits, primarily due to its antioxidant, anti-inflammatory, antiviral, and anticancer properties.

In plants, quercetin serves as a protective substance, defending against microbial infections and environmental stress. For humans, it’s predominantly obtained through the consumption of foods such as onions, apples, berries, and teas. Its biological roles in human health are vast, with studies suggesting benefits ranging from anti-aging and anti-inflammatory effects to potential protective roles against various diseases.

Natural Occurrence and Derivatives

Quercetin is naturally found in various plants, primarily as glycosides, where the quercetin molecule is bound to a sugar molecule, enhancing its solubility and transport within the plant. These glycosides are metabolized to free quercetin in the human digestive system when consumed through the diet. Notable sources of quercetin include onions, apples, berries, and tea, among others. The presence of quercetin in these forms in plants underscores its relevance in plant physiology, particularly in providing protection against oxidative stress and contributing to the pigmentation in plant tissues.

Foods	Quercetin Content (mg / 100 g)
Capers (Raw)	234
Capers (Canned)	173
Lovage Leaves (Raw)	170
Dock (Sorrel-like)	86
Radish Leaves	70
Carob Fiber	58
Dill Weed (Fresh)	55
Coriander	53
Yellow Wax Pepper (Raw)	51
Fennel Leaves	49
Onion (Red)	32
Radicchio	32
Watercress	30
Kale	23
Chokeberry	19
Bog Blueberry	18
Buckwheat Seeds	15
Cranberry	15
Lingonberry	13
Plums (Black)	12

In red onions, higher concentrations of quercetin occur in the outermost rings and in the part closest to the root, the latter being the part of the plant with the highest concentration. One study found that organically grown tomatoes had 79% more quercetin than non-organically grown fruit. Quercetin is present in various kinds of honey from different plant sources.

Background Intake

Quercetin is one of the most abundant dietary flavonoids. To estimate the average quercetin intake of the U.S. population, data from the flavonoid database was combined with food consumption data from the 2003-2004 National Health and Nutrition Examination Surveys (NHANES). Only individuals who reported consuming foods naturally rich in quercetin were included in the analysis.

The table below presents the estimated daily quercetin intake from natural sources for various U.S. population groups. The overall consumption of quercetin-rich foods led to an estimated average intake of 5.9 mg/person/day, with the 90th percentile at 14.7 mg/person/day. The highest reported individual intake was 258.2 mg/day, observed in the adult male group. It's worth noting that these estimates might be on the conservative side, as quercetin content data is available only for select foods.

Estimated Daily Background Intake of Quercetin from Naturally Occurring Sources in the United States by Population Group

Population Group	Age Group (Years)	% Users	Background Quercetin Intake (Users Only)
			Mean (mg)	90th Percentile (mg)	Maximum (mg)
Infants	0 - 2	54.2	1.9	3.7	60.2
Children	3 - 11	85.5	2.6	6.3	96.4
Female Teenagers	12 - 19	79.6	4.9	10.7	176.8
Male Teenagers	12 - 19	83.9	6.1	15.1	118.2
Female Adults	20+	82.4	5.7	15.6	117.5
Male Adults	20+	84.0	7.6	17.8	258.2
Total Population	All Ages	79.9	5.9	14.7	258.2

Chemical and Physical Properties

Quercetin possesses distinct chemical and physical properties, integral to its bioactivity and its interaction within biological systems.

• Molecular Structure: Quercetin has a molecular formula of C₁₅H₁₀O₇ and is composed of two phenyl rings (A and B) bonded to a heterocyclic ring (C) containing one oxygen atom, forming a structure typical of flavonoids. Its full chemical name is 3,3',4',5,7-pentahydroxyflavone.

• Solubility and Stability: Quercetin has limited solubility in water but is soluble in organic solvents like ethanol. It is relatively stable in acidic conditions but is susceptible to degradation in basic conditions and under exposure to light and heat. Its stability is crucial for its absorption and bioavailability, as well as its effectiveness in various formulations.

• Molecular Weight: The molecular weight of quercetin is approximately 302.24 g/mol, a factor that influences its distribution and metabolism within the body.

Pharmacological Properties

The pharmacological properties of Quercetin have sparked extensive research due to its potential therapeutic applications. Here we explore its absorption, metabolism, elimination, and mode of action within the body.

Poor Bioavailability of Standard Quercetin

Quercetin's bioavailability is complex, influenced largely by its poor water solubility, which results in low absorption and extensive metabolism, hence reducing its availability to exert biological effects. It is predominantly found in foods as glycosides, bound to sugar molecules, which impacts its absorption and subsequent bioavailability.

In a clinical study with a different formulation of quercetin (Quercetin Phytosome) a ~20 fold relative bioavailability compared to standard quercetin was measured. Given that Quercetin Phytosome contains ~40% quercetin, one can assume that the total bioavailability of standard quercetin is less than 2%.

Quercetin, when consumed, undergoes an absorption process primarily in the small intestine. The glycosidic form of quercetin needs to be hydrolyzed by β-glucosidase to its aglycone form before absorption. Once hydrolyzed, it is absorbed through enterocytes via passive diffusion or through active transport mechanisms. The overall absorption of quercetin is estimated to be relatively low, varying between individuals and dependent on dietary matrix and presence of other flavonoids.

Once absorbed, quercetin undergoes extensive first-pass metabolism in the liver and intestines, where it is converted into various metabolites through glucuronidation, sulfation, and methylation. The extensive metabolism significantly reduces the concentrations of free quercetin in the plasma, limiting its bioavailability. The metabolites, however, may retain some biological activity and contribute to the overall effects of quercetin in the body.

Formulation of Enhanced Bioavailability

The low bioavailability of quercetin raises questions about the clinical relevance of its potential health benefits observed in vitro and in animal studies. Therefore, several strategies have been explored to enhance the absorption and stability of quercetin. The following formulations are found on the market:

Formulation	Alternative Names	Relative Bioavailability	Solubility in Water	Notes
Standard Quercetin		1 (baseline)	Very Low	Naturally occurring in various plants; serves as the baseline form of quercetin with poor solubility and bioavailability.
Quercetin Dihydrate		–	Moderate	Synthetic form with two water molecules associated; usually preferred for dietary supplements due to improved solubility.
Quercetin Phytosomes	Quercetin-Phospholipid	10-20	Improved	Significantly increases oral bioavailability compared to standard quercetin.
Nanoparticle Formulations	Nanoquercetin, Quercetin Nanocapsules	Several-fold increase	Variable, generally improved	Includes liposomal encapsulations; increased solubility and cellular uptake.
Quercetin LipoMicel		8-9		Encapsulating quercetin within a liquid micelle matrix
Co-administration with Piperine	Bioavailability Enhanced Quercetin, Piperine-Quercetin Combination	Approximately 20%	Low	Inhibits metabolism of quercetin, improving its bioavailability.

Quercetin Phytosome

Pharmacokinetic profile of standard quercetin and quercetin phytosome in the clinical study. The plasma concentrations of quercetin obtained after single oral administration of the unformulated quercetin at 500 mg/tablet and after single oral administration of its corresponding lecithin formulation, Quercetin Phytosome, at a dose of either 500 or 250 mg are shown.

Quercetin Phytosome is a formulation where quercetin is bound to phospholipids, typically derived from sunflower or soy lecithin, to enhance its bioavailability and absorption. The relevant clinical study used Quercetin Phytosome (QUERCEFIT™) consisting of quercetin and sunflower lecithin in a 1:1 weight ratio along with about a fifth part of food-grade excipients that are added to improve the physical state of the product and to standardize it to an HPLC-measured total quercetin content of about 40%. In the clinical study, a ~20-fold increase in bioavailability was measured compared to standard quercetin with equal doses.

Pharmacokinetic parameters (noncompartmental model)

	Quercetin 500 mg	Quercetin Phytosome 500 mg	Quercetin Phytosome 250 mg
AUClast (min × ng/ml)	4774.93 ± 1190.61	96,163.87 ± 9291.31	50,401.53 ± 6418.22
Cmax (ng/ml)	10.93 ± 2.22	223.10 ± 16.32	126.35 ± 14.79*
Tmax (min)	290.00 ± 31.19	202.50 ± 35.97	228.75 ± 36.61
t1/2 (min)	375.63 ± 75.51	226.84 ± 8.13	201.63 ± 13.18
MRT last (min)	410.41 ± 24.24	372.94 ± 20.12	386.29 ± 21.04

Quercetin Phytosome overcomes the low bioavailability hurdle of quercetin and should help to fulfill the great health benefit potential of this flavonoid in the diet and as food supplements.

Quercetin LipoMicel

Quercetin LipoMicel is a novel formulation from Natural Factors designed to enhance the bioavailability of quercetin. LipoMicel encapsulates quercetin molecules within micelles, tiny spherical structures formed from natural, non-ionic surfactants. These micelles facilitate the solubilization of quercetin, allowing it to be more readily absorbed in the gastrointestinal tract. In a study sponsored by Natural Factors, the bioavailability of Standard Quercetin, Quercetin Phytosome and Quercetin LipoMicel was compared. Thereby, Quercetin Phytosome had a slightly higher relative bioavailability (AUC) than for Quercetin LipoMicel, but longer steady state levels of quercetin were provided by LipoMicel.

Pharmacokinetic parameters

	Quercetin 500mg	Quercetin LipoMicel 500mg	Quercetin Phytosome 500mg
AUC0-24 (ng h/ml)	172.87 ± 12.21	1477.27 ± 25.57	1536.00 ± 115.66
Cmax (ng/ml)	19.77 ± 27.29	182.85 ± 106.64	150.27 ± 61.43
Tmax (hours)	2 ± 0.15	0.5 ± 0.02	1 ± 0.30
t1/2 (hours)	11.66 ± 0.55	8.29 ± 0.49	6.02 ± 0.52

Clinical Applications and Effects on Longevity

Quercetin has been the focus of numerous clinical studies aiming to understand its potential applications and efficacy in addressing age-related conditions and promoting longevity due to its diverse biological activities.

Anti-inflammatory Effects

Quercetin’s potent anti-inflammatory properties have led to its investigation for use in chronic inflammatory conditions such as arthritis and cardiovascular diseases. It modulates inflammatory pathways by inhibiting the release of pro-inflammatory cytokines and reducing the activation of inflammatory cells.

Antioxidant Properties

The antioxidant activity of quercetin is attributed to its ability to neutralize free radicals and reduce oxidative stress, potentially mitigating aging-related cellular damage and dysfunction. Its antioxidant properties are linked to a reduction in the risk of chronic conditions such as cancer and neurodegenerative diseases.

Impact on Cellular Senescence

Research has indicated that quercetin may delay cellular senescence by modulating senescence-associated signaling pathways and reducing the accumulation of senescent cells, potentially impacting aging processes and age-related diseases.

Clinical Studies and Trials related to Aging

Several clinical trials and studies have been conducted to assess the safety and efficacy of quercetin supplementation in age-related conditions. The data, however, are still inconclusive, necessitating further well-designed studies to establish its therapeutic benefits in aging and longevity comprehensively.

Role as an NAD+ Booster

Quercetin has been identified as a potential NAD+ booster. Studies have demonstrated that quercetin can inhibit the activity of NADase (CD38), an enzyme responsible for the degradation of NAD+, thus potentially increasing the levels of NAD+ in cells. Elevated NAD+ levels are associated with improved mitochondrial function, enhanced cellular metabolism, and reduced oxidative stress, all of which are key components in the aging process.

Dosage and Administration

Exploring the optimal dosage and various administration forms is crucial for leveraging the potential benefits of Quercetin. Given the variances in individual responses and bioavailability, establishing the right dosage is paramount.

Recommended Dosages

Typical supplemental dosages of quercetin range from 500 to 1000 mg per day, usually divided into multiple doses. However, optimal dosages may vary based on individual health conditions, goals, and sensitivities, and consultation with a healthcare provider is advised for personalized recommendations.

Administration Forms and Bioavailability Enhancement

Quercetin is available in various forms, including tablets, capsules, and powders. To enhance its bioavailability, it is often formulated with bioflavonoids or bromelain, or encapsulated in liposomes or phytosomes. Different formulations may affect the absorption and efficacy of quercetin, and choosing the right form is crucial for optimal results.

Safety and Side Effects

Understanding the safety profile and potential side effects of Quercetin is vital for informed supplementation. While generally regarded as safe, quercetin may cause adverse reactions in certain situations or populations.

In 2010, the FDA acknowledged high-purity quercetin (≥ 99.5% quercetin) as Generally Recognized as Safe (GRAS) for use as an ingredient in various specified food categories at levels up to 500 milligrams per serving.

Known Side Effects

In some individuals, quercetin supplementation can lead to side effects such as headaches, stomach pain, and tingling of the extremities. Rarely, it may cause kidney damage at high doses.

Interactions with Medications and Other Supplements

Quercetin has the potential to interact with various medications, including antibiotics and blood pressure medications, potentially altering their effects. Additionally, its interaction with other supplements, particularly those with similar biological effects, needs careful consideration to avoid cumulative effects or imbalances.

Safety Precautions and Contraindications

Individuals with kidney conditions, pregnant or breastfeeding women, and those on specific medications should consult healthcare providers before starting quercetin supplementation. Proper dosage and adherence to safety precautions are crucial to minimize the risk of adverse reactions.

Conclusions and Future Directions

Quercetin has garnered substantial attention in the realm of longevity and health due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and potential anti-aging properties.

Summary of Key Findings

Quercetin’s diverse pharmacological properties, such as modulation of inflammatory pathways, neutralization of free radicals, and potential impact on cellular senescence, offer promising avenues for addressing age-related conditions and promoting health and longevity. However, the conclusive benefits and optimal dosages in humans are yet to be firmly established.

Gaps in Current Knowledge and Research

While quercetin’s therapeutic potential is evident from preclinical and some clinical studies, significant gaps persist in our understanding of its precise mechanisms of action, long-term safety, and efficacy in humans. Further well-designed clinical trials and comprehensive studies are imperative to bridge these gaps and validate quercetin's roles in human health and longevity.

Future Directions and Potential Implications

The ongoing and future research on quercetin is poised to explore novel formulations and delivery methods to improve its bioavailability and therapeutic efficacy. The elucidation of its molecular targets and mechanisms will facilitate the development of targeted interventions for age-related diseases and conditions, potentially impacting healthcare approaches and strategies for healthy aging.

Quercetin remains a compelling subject in the longevity and health science field, with its future promising to unveil deeper insights into its biological activities and therapeutic potentials, possibly leading to innovative solutions for aging and age-associated ailments.