Phloretin

• Potent antioxidant protection
• Anti-inflammatory effects
• Glucose metabolism regulation
• Cellular stress resistance

• Neuroprotection
• Cardiovascular health support
• Antimicrobial properties
• Potential anticancer effects
• Skin protection

Phloretin exerts its biological effects through multiple molecular mechanisms. As a potent antioxidant, phloretin directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), neutralizing free radicals that can damage cellular components. Its planar structure with multiple hydroxyl groups enables efficient electron donation to neutralize free radicals. Beyond direct scavenging, phloretin enhances endogenous antioxidant defense systems by activating nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular redox homeostasis.

This activation increases the expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, and heme oxygenase-1. Phloretin’s anti-inflammatory properties stem from its ability to inhibit nuclear factor-kappa B (NF-κB) activation, a key regulator of inflammatory responses. This inhibition reduces the expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Phloretin also suppresses the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), further reducing inflammatory mediator production.

One of phloretin’s most distinctive mechanisms is its ability to inhibit facilitative glucose transporters (GLUTs), particularly GLUT1 and GLUT2. By blocking these transporters, phloretin reduces glucose uptake in various cell types, which has implications for metabolic regulation and potential anticancer effects, as many cancer cells rely heavily on glucose for energy. In metabolic regulation, phloretin activates AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, which improves insulin sensitivity, enhances fatty acid oxidation, and reduces lipogenesis. It also inhibits pancreatic α-amylase and intestinal α-glucosidase, enzymes involved in carbohydrate digestion, contributing to its anti-hyperglycemic effects.

Phloretin’s neuroprotective properties are mediated through multiple pathways, including reduction of oxidative stress in neural tissues, inhibition of neuroinflammation, and protection against amyloid-beta toxicity. It enhances brain-derived neurotrophic factor (BDNF) levels, supporting neuronal health and plasticity. In cancer cells, phloretin induces cell cycle arrest and apoptosis through modulation of various signaling pathways including PI3K/Akt, MAPK/ERK, and JAK/STAT. Its ability to inhibit glucose uptake in cancer cells by blocking GLUTs may contribute to its anticancer effects by starving cancer cells of their primary energy source.

Phloretin also exhibits antimicrobial properties against various pathogens through disruption of bacterial cell membranes and inhibition of bacterial enzymes. It has been shown to enhance the efficacy of certain antibiotics when used in combination. Additionally, phloretin modulates epigenetic mechanisms by inhibiting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), potentially reversing aberrant epigenetic modifications associated with various diseases. In skin cells, phloretin protects against UV-induced damage by absorbing UV radiation, scavenging ROS generated by UV exposure, and activating DNA repair mechanisms.

It also inhibits matrix metalloproteinases (MMPs) that degrade collagen and elastin, contributing to its anti-aging effects on skin.

There is no established standard dosage for phloretin as a standalone supplement for general health purposes. Most research has been conducted using apple extracts containing phloretin among other compounds, or in animal and in vitro studies using various doses. Based on preliminary research and limited clinical studies, typical supplemental doses range from 50-200 mg of phloretin daily, though this is not well-established in human clinical trials.

For general health benefits, phloretin can be taken with meals to improve tolerance and potentially enhance absorption. For blood glucose management, taking before meals may help reduce postprandial glucose spikes. Dividing the daily dose into two administrations (morning and evening) may provide more consistent effects throughout the day.

There is insufficient evidence to make specific recommendations about cycling phloretin supplementation. For long-term use, consider periodic breaks (e.g., 1 week off after 8-12 weeks of supplementation) to prevent potential adaptation or tolerance development.

Taking with meals containing fat may enhance absorption due to phloretin’s lipophilic nature. Avoid taking with high-sugar foods or beverages, as this may counteract some of the glucose-regulating benefits. Some evidence suggests that certain polyphenols in tea may enhance phloretin’s effects through synergistic antioxidant activity.

Phloretin has relatively low oral bioavailability, with absorption rates typically ranging from 5-15% of ingested amounts. This limited bioavailability is primarily due to its chemical structure, poor water solubility, extensive first-pass metabolism, and degradation in the gastrointestinal environment. After oral administration, phloretin undergoes significant metabolism in the intestinal epithelium and liver before reaching systemic circulation.

Consumption with dietary fats: Taking phloretin with a meal containing moderate fat content can enhance absorption by up to 30-50% by improving solubility and lymphatic transport., Micronization: Reducing particle size to micro or nano scale increases surface area and improves dissolution rates, potentially enhancing bioavailability by 50-100%., Liposomal formulations: Encapsulation in phospholipid bilayers can protect phloretin from degradation in the gastrointestinal tract and enhance cellular uptake., Phytosome technology: Complexing with phospholipids creates a more lipid-compatible molecular complex that improves absorption across intestinal membranes., Co-administration with piperine: Black pepper extract can inhibit enzymes involved in phloretin metabolism, potentially increasing bioavailability by 30-60%., Emulsion-based delivery systems: Oil-in-water emulsions can improve solubility and protect from degradation in the gastrointestinal environment., Cyclodextrin complexation: Forms inclusion complexes that protect phloretin from degradation and improve solubility., Consumption with quercetin or other flavonoids: May compete for the same metabolic enzymes, potentially increasing phloretin’s half-life and bioavailability., Topical application: For skin benefits, topical application bypasses gastrointestinal absorption issues and delivers phloretin directly to the target tissue.

For general health benefits, phloretin-containing supplements are best taken with meals to maximize absorption. For blood glucose management, taking 15-30 minutes before meals may help modulate postprandial glucose response. Splitting the daily dose into two administrations (morning and evening) may provide more consistent blood levels throughout the day.

After absorption, phloretin undergoes extensive phase I and phase II metabolism, primarily in the liver. The main metabolic pathways include glucuronidation, sulfation, and methylation. The resulting metabolites may retain some biological activity but often have different pharmacological profiles compared to the parent compound. Phloretin and its metabolites are primarily excreted through urine and bile.

The plasma half-life of phloretin is relatively short, typically 2-4 hours, although some metabolites may persist longer. Unabsorbed phloretin reaches the colon where it is metabolized by gut microbiota into various phenolic acids, which may have their own biological activities and better absorption profiles.

Individual genetic variations in metabolizing enzymes, particularly UDP-glucuronosyltransferases and sulfotransferases, Age (generally lower bioavailability in older adults due to reduced intestinal absorption and hepatic metabolism), Gut microbiome composition, which affects the conversion of phloretin to metabolites in the colon, Concurrent medications, particularly those affecting gastric pH or liver enzymes, Gastrointestinal health and transit time, Food matrix (whole foods vs. isolated compounds), Processing methods of source materials (heat treatment can reduce content), Storage conditions and age of supplement (degradation over time)

Phloretin and its metabolites show preferential distribution to the liver, kidneys, and intestinal tissues. Lower concentrations are found in the brain, suggesting limited blood-brain barrier penetration,

although some neuroprotective effects have been observed in animal studies. The compound and its metabolites can also be detected in adipose tissue, skeletal muscle, and the heart, though at lower concentrations compared to the primary target organs.

When applied topically, phloretin can penetrate the stratum corneum and reach viable epidermis and dermis, making

it effective for dermatological applications.

• Gastrointestinal discomfort (rare, typically at high doses)
• Mild headache (uncommon)
• Potential hypoglycemia, especially when combined with diabetes medications
• Mild diarrhea or loose stools (due to effects on glucose transport in intestine)
• Allergic reactions (very rare, more common in individuals with apple allergies)
• Temporary changes in taste perception (uncommon)

• Known allergy to apples or related fruits
• Caution in diabetes (may affect blood glucose levels)
• Caution in individuals with hypotension (may enhance blood pressure-lowering effects)
• Pregnancy and lactation (insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential glucose effects)
• Severe liver or kidney disease (may affect metabolism and excretion)

• Antidiabetic medications (insulin, sulfonylureas, metformin): May enhance hypoglycemic effects, requiring dose adjustments
• Antihypertensive medications: Potential additive hypotensive effects
• Antibiotics: May enhance the efficacy of certain antibiotics, particularly against resistant strains
• Cytochrome P450 substrates: May inhibit certain CYP enzymes, potentially affecting drug metabolism
• P-glycoprotein substrates: May inhibit P-gp, potentially increasing absorption of certain drugs
• NSAIDs: Potential additive anti-inflammatory effects, but also potential for increased risk of gastrointestinal side effects
• Anticoagulants/antiplatelets: Theoretical risk of enhanced antiplatelet effects, though clinical significance is unclear

No established upper limit for phloretin specifically. Based on available research, doses up to 300 mg daily have been used in short-term studies without serious adverse effects. However, caution is advised with doses exceeding 200 mg daily, particularly in individuals with pre-existing health conditions or those taking medications.

Long-term safety data specific to phloretin supplementation is limited. Most studies have been short-term (up to 12 weeks). Given its presence in commonly consumed foods like apples, phloretin is generally considered safe for long-term consumption at dietary levels. For supplemental doses, regular monitoring is recommended for individuals using high doses long-term.

Acute toxicity studies in animal models have shown low toxicity. The LD50 (median lethal dose) in rodents is extremely high, indicating low acute toxicity risk. Genotoxicity studies have not shown mutagenic or clastogenic potential. Carcinogenicity studies have not indicated any cancer-promoting effects; in fact, evidence suggests potential anti-cancer properties.

Allergic reactions to phloretin are rare but possible, particularly in individuals with existing apple allergies. Symptoms may include skin rash, itching, swelling, dizziness, or difficulty breathing. Discontinue use immediately if allergic reactions occur.

For individuals taking phloretin supplements regularly, particularly at higher doses, periodic monitoring of the following is recommended: blood glucose levels, liver function tests, kidney function, and blood pressure. Those with pre-existing medical conditions or taking medications should consult healthcare providers before starting supplementation.

Phloretin is not specifically approved as a pharmaceutical drug by the FDA. It falls under the category of dietary supplements regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As a dietary supplement ingredient, manufacturers cannot make specific disease treatment claims but can make structure/function claims with appropriate disclaimers. The FDA does not review or approve dietary supplements containing phloretin before they enter the market.

For cosmetic applications, phloretin is permitted as an ingredient in topical formulations. Phloretin from apple sources is generally recognized as safe (GRAS) when used in food products, as it is naturally present in apples and apple products that have a long history of safe consumption.

Eu: In the European Union, phloretin is regulated under the European Food Safety Authority (EFSA) as a food constituent. As a supplement ingredient, phloretin falls under the Food Supplements Directive (2002/46/EC). For cosmetic applications, it is listed in the European Inventory of Cosmetic Ingredients. No approved health claims specific to phloretin have been authorized by EFSA. Novel food applications would be required for phloretin sources not traditionally consumed in the EU before May 1997, though apple extracts generally do not fall under this requirement.

Canada: Health Canada regulates phloretin-containing supplements under the Natural Health Products Regulations. Products containing phloretin must have a Natural Product Number (NPN) to be legally sold. Health Canada has not approved specific claims for phloretin, though some general claims for apple polyphenols may be permitted. For cosmetic applications, phloretin is permitted as an ingredient in topical formulations.

Australia: The Therapeutic Goods Administration (TGA) regulates phloretin-containing supplements as complementary medicines. Products must be listed or registered on the Australian Register of Therapeutic Goods (ARTG). Traditional claims based on historical use may be permitted with appropriate evidence. Food Standards Australia New Zealand (FSANZ) oversees phloretin when used as a food ingredient.

Japan: In Japan, phloretin-containing supplements may be regulated as Foods with Health Claims, specifically as Foods with Functional Claims (FFC) if scientific evidence supports specific health benefits. Manufacturers must notify the Consumer Affairs Agency before marketing such products. For cosmetic applications, phloretin is permitted as an ingredient in topical formulations.

China: The China Food and Drug Administration (CFDA) regulates phloretin-containing supplements. New ingredients may require extensive safety testing before approval. For cosmetic applications, phloretin is included in the Inventory of Existing Cosmetic Ingredients in China (IECIC).

Usa: Supplements containing phloretin must be labeled as dietary supplements and include a Supplement Facts panel. Structure/function claims must be accompanied by the disclaimer: ‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’ Manufacturers are responsible for ensuring that any claims are truthful and not misleading.

Eu: Products must be labeled as food supplements and include a Nutrition Facts panel. Any claims must comply with the Nutrition and Health Claims Regulation (EC) No 1924/2006. The term ‘apple polyphenols’ is more commonly used on labels than specific compounds like phloretin.

General: Most jurisdictions require listing of all ingredients, appropriate storage conditions, expiration dates, and manufacturer contact information. Allergen information must be provided if relevant (e.g., if the product contains other apple components that might trigger apple allergies).

Disease treatment claims are prohibited in most jurisdictions without pharmaceutical approval. Claims regarding diabetes treatment or prevention are particularly scrutinized and generally not permitted for supplements. Structure/function claims must be supported by scientific evidence, though the standard of evidence varies by country. In the EU, health claims are more strictly regulated and must be pre-approved based on substantial scientific evidence.

Claims regarding children’s health are generally more restricted across all jurisdictions. Anti-aging and longevity claims are scrutinized carefully by regulatory authorities.

Cross-border trade of phloretin-containing supplements may be subject to varying regulatory requirements. Products compliant in one jurisdiction may not meet the requirements of another. Some countries require pre-market registration or notification for imported supplements. Customs documentation should clearly identify the nature of the product and its ingredients.

Increasing regulatory focus on quality control and standardization of botanical extracts containing compounds like phloretin. Growing interest in personalized nutrition may lead to more nuanced regulatory approaches for different population groups. Potential for more specific health claims as research evidence accumulates. Increasing harmonization of regulations across major markets to facilitate international trade.

Greater scrutiny of glucose-modulating supplements due to their potential interaction with diabetes medications.

For topical applications, phloretin is regulated as a cosmetic ingredient in most jurisdictions. In the EU, it is included in the European Inventory of Cosmetic Ingredients. In the US, it falls under FDA cosmetic regulations. Claims for topical products are generally more permissive than for oral supplements, though anti-aging and skin protection claims still require substantiation. Combination products with vitamin C and ferulic acid have established regulatory precedent in many markets.

Medium to High

Pure phloretin supplements are relatively rare in the market. Most supplements contain apple extracts standardized to contain specific percentages of phloretin along with other polyphenols. For standardized apple extracts (typically 1-5% phloretin), the cost ranges from $0.75 to $2.50 per effective daily dose. Enhanced bioavailability formulations (liposomal, phytosomal) typically cost $2.00 to $5.00 per effective daily dose.

Topical formulations containing phloretin (often combined with vitamin C and ferulic acid) range from $1.50 to $8.00 per application, with high-end cosmeceutical brands commanding premium prices.

The cost-effectiveness of phloretin supplementation depends largely on the specific health goals and individual factors. For general antioxidant support, less expensive apple polyphenol blends may provide adequate value. For specific applications requiring higher bioavailability, premium formulations may offer better value despite higher costs. Whole food sources (apples, particularly the peels) provide the most cost-effective way to consume phloretin along with complementary compounds, though exact dosing is less precise and concentrations are much lower than in supplements.

For topical applications, the combination with vitamin C and ferulic acid has well-documented efficacy for photoprotection and anti-aging effects, potentially justifying the higher cost compared to single-ingredient products. The relatively short half-life of phloretin means that consistent, regular supplementation is necessary for ongoing benefits, which should be factored into long-term cost considerations.

Price Trends: Prices for apple extracts containing phloretin have generally remained stable over the past decade, with slight increases due to growing demand for polyphenol supplements. Premium formulations with enhanced bioavailability continue to command higher prices. In the cosmetic sector, phloretin-containing formulations have seen significant price variation, with high-end brands charging premium prices for essentially similar formulations.

Regional Variations: Prices tend to be higher in North America and Europe compared to Asian markets. Local availability of apple sources significantly impacts regional pricing. Regulatory requirements in different regions affect production costs and final pricing.

Economy Of Scale: Bulk purchasing can significantly reduce costs, with discounts of 20-40% common for larger quantities. Subscription services often offer 10-15% discounts for regular purchases.

Purchase during seasonal sales, which can offer discounts of 15-30%, Consider bulk purchases for non-perishable forms, Subscribe to regular delivery services for consistent discounts, Combine dietary sources (apples with peels) with lower supplement doses, Focus on enhanced bioavailability formulations that may allow for lower effective doses, Look for combination products that provide synergistic compounds in a single formula, For topical applications, consider mid-range brands that offer the same key ingredients (phloretin, vitamin C, ferulic acid) as premium brands at lower prices, Make DIY apple peel tea or extract by simmering organic apple peels in water (though concentration will be variable)

Most health insurance plans do not cover phloretin or apple polyphenol supplements. Some Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) may allow purchase of supplements with a doctor’s recommendation, though policies vary widely. Certain integrative medicine practitioners may prescribe specific formulations that could qualify for reimbursement under some plans. For topical formulations prescribed for specific skin conditions, some insurance plans may provide partial coverage, though cosmetic applications are generally not covered.

Compared to other polyphenol supplements like quercetin or resveratrol, phloretin supplements tend to be similarly priced or slightly more expensive. For general antioxidant support, other options like vitamin C or mixed tocopherols may provide better value,

while phloretin offers more specific benefits for glucose metabolism and certain cellular pathways. For topical applications, the combination with vitamin C and ferulic acid has stronger evidence for efficacy than many other anti-aging ingredients, potentially justifying the higher cost.

Phloretin and phloretin-containing supplements typically have a shelf life of 18-24 months when properly stored. However, degradation begins immediately after production, with approximately 5-15% loss of active content per year under optimal storage conditions.

Store in airtight, opaque containers to protect from light, oxygen, and moisture. Refrigeration (2-8°C) is recommended to slow degradation, particularly after opening. Freezing (-18°C or below) can further extend stability for long-term storage. Avoid temperature fluctuations, which can accelerate degradation through condensation cycles. Keep away from strong-smelling substances as phloretin can absorb odors that may affect sensory properties.

Color change is a visible indicator of degradation, with phloretin shifting from pale yellow to darker brown as it oxidizes. However, some degradation can occur without visible color change. Analytical methods like HPLC or spectrophotometry are more reliable for quantifying remaining active content. Development of off-odors or flavors may indicate degradation or microbial contamination. Clumping or hardening of powder formulations suggests moisture exposure.

For powdered supplements, reconstituted solutions should be used within 24-48 hours and kept refrigerated. Stability in solution is significantly lower than in dry form. Acidification of the reconstitution liquid (e.g., with citric acid) can improve stability. Protection from light remains important after reconstitution.

Heat processing significantly reduces phloretin content, with losses of 30-70% reported during cooking or pasteurization of apple products. Freeze-drying preserves more phloretin than heat drying methods. Mechanical processing that exposes the compound to oxygen (e.g., grinding, juicing) accelerates degradation unless antioxidant protection is provided. For topical formulations, stability is enhanced

when combined with complementary antioxidants like vitamin C and ferulic acid in properly formulated vehicles.

Synthesis Methods

Natural Sources

Quality Considerations

Sustainability Considerations

While phloretin itself was not specifically identified until modern analytical techniques became available, apples and apple products containing phloretin have a long history of traditional use across various cultures. The ancient saying ‘an apple a day keeps the doctor away’ reflects the long-standing recognition of apples’ health benefits, which we now know are partly attributable to bioactive compounds like phloretin. In traditional European folk medicine, apple preparations were used for digestive ailments, fever reduction, and as a general health tonic. Native American tribes incorporated wild apples and crabapples into their medicinal practices, using them to treat various conditions including digestive disorders and respiratory ailments.

In traditional Chinese medicine, apples were considered cooling and moistening, used to quench thirst, prevent indigestion, and detoxify the body. They were particularly recommended for lung and stomach conditions. The scientific history of phloretin began in the early 20th century when it was first isolated and characterized from apple tree bark. Initially, it was primarily studied for its chemical properties rather than medicinal applications.

In the 1950s and 1960s, researchers discovered phloretin’s ability to inhibit glucose transport across cell membranes, which made it a valuable tool in biochemical research for studying membrane transport mechanisms. This property later became the basis for understanding some of its potential health benefits. The 1970s and 1980s saw increased research into phloretin’s antioxidant properties, as scientific interest in dietary antioxidants grew. However, it remained primarily a research compound rather than a therapeutic agent.

In the 1990s, as research into polyphenols expanded, phloretin began to receive more attention for its potential health benefits beyond its glucose transport inhibition properties. Studies began to explore its antioxidant, anti-inflammatory, and potential anticancer effects. The early 2000s marked the beginning of phloretin’s use in cosmetic and dermatological applications. Its antioxidant properties and ability to penetrate the skin made it valuable for photoprotection and anti-aging formulations.

The first commercial topical products containing phloretin, often in combination with vitamin C and ferulic acid, were introduced during this period. In the 2010s, research into phloretin’s metabolic effects expanded, with studies exploring its potential benefits for diabetes, obesity, and related conditions. This coincided with growing interest in natural compounds for managing these increasingly prevalent health issues. More recently, phloretin has gained attention for its potential neuroprotective effects and role in cellular stress resistance, aligning with the growing scientific interest in compounds that may support healthy aging and longevity.

Today, phloretin is found in various supplements, often as part of apple extracts, and in numerous topical formulations for skin health. It continues to be studied for its diverse biological activities and potential therapeutic applications across multiple health domains.

Boyer, J., et al. (2004). Apple phytochemicals and their health benefits. Nutrition Journal, 3(1), 5., Williamson, G., et al. (2018). Dietary polyphenols: A new strategy for the prevention and treatment of type 2 diabetes? Molecular Nutrition & Food Research, 62(1), 1700976.

NCT04255069: Effects of Apple Polyphenols on Glucose Metabolism in Pre-diabetic Individuals, NCT03865355: Apple Polyphenol Extract Supplementation and Cognitive Function in Older Adults, ISRCTN72366225: Phloretin-enriched Apple Extract for Improving Metabolic Health in Overweight Adults

Limited human clinical trials specifically examining isolated phloretin rather than apple extracts containing multiple compounds, Insufficient dose-response studies to establish optimal therapeutic dosages in humans, Limited long-term safety and efficacy data beyond 12 weeks of supplementation, Incomplete understanding of interactions with medications and other supplements, Need for bioavailability studies comparing different delivery systems, Limited research on genetic factors affecting individual responses to phloretin supplementation, Insufficient data on phloretin’s effects in specific populations such as the elderly or those with existing health conditions