scientific evidence

literature and references

1

Polypodium Leucotomos Extract (PLE)

Background

Polypodium leucotomos (PL) is a fern native to Central and South America where it has a historical role in traditional medicine. Polypodium leucotomos extract (PLE) is composed of phenolic compounds and acid molecules notably p-coumaric, ferulic, caffeic, and vanillic acid. Its chemical composition endows it with photoprotective qualities. It has been studied extensively in both topical and oral formulations in in-vivo human and murine models. It is absorbed rapidly and efficiently (70-100%) and metabolized in 24 hours by the liver(1).  It is currently available in topical and oral formulations and has been utilized in Europe for over a decade. 

Clinical Features

  • Actinic Keratosis: Reduction in new AK development over 6 and 12 mo in patients with severe actinic damage when combined with SPF 100 compared to SPF 100 alone(2).
  • UV Erythema Tolerance: PLE increases minimal erythemal dose (MED) in human UV erythema testing(3).
  • Delays UVR-induced tumor development in mice(4).
  • Protection from visible light damage (such as blue light from digital devices)(1).
  • Also demonstrated to have applications for vitiligo, PMLE, and other photosensitive conditions with regard to light tolerance.

Dosing

  • Recommended oral dose is 240mg daily in the morning. When excessive sun exposure is expected, 240mg is recommended one hour before exposure and after 2-3 hrs. 
  • Topically available as sunscreen booster 

Safety

  • PLE has a good safety profile without side effects and has been shown to be safe in children. No data is available with pregnancy(5, 6, 7).

Mechanism of Action

  • Antioxidant(8, 9): due to polyphenolic compounds and is able to inhibit membrane damage and lipid peroxidation in fibroblasts and keratinocytes1 PLE is also a direct ROS scavenger against superoxide anion, hydrozyl oxygen and oxygen peroxide and results in reduced levels of 8-OH-dG, a marker of cellular oxidative damage1  
  • Reduction in DNA Damage (8, 9):  Reduction of cyclobutane pyrimidine dimer (CPD) production after UVR10 induces activation of oncosuppressor p53 and decreases UV induced mitochondrial DNA damage as well(1)
  • Immunomodulatory Activity: Inhibition of t-UCA isomerization11 decreases UV-induced COX-2 expression(1)
  • Protection of skin immunosurveillance: (prevention of immune cell depletion upon UV irradiation)(8, 12, 13)
  • Extracellular Matrix: Inhibits MPP-1,2,3 and 9 and stimulates TGF-b, elastin and fibrillin(1)
  • Visible Light Protection: inhibits increase in MMP-1, protects fibrillin and elastin, reduces opsin-3 activation, preventing melanin photooxidation and photodegradation in human cell lines(1)
2

Niacinamide

Background

Niacinamide (NAM) is the amide form of niacin (vitamin B3). NAM is distinct from niacin and does not cause flushing. Niacinamide is a precursor for nicotinamide adenine dinucleotide (NAD+), which is an essential coenzyme in cellular energy production. Adequate cellular ATP is essential for DNA synthesis and repair. After UV radiation, a cellular energy crisis occurs which restricts DNA repair. Studies demonstrate that niacinamide supplementation is able to prevent the energy crisis and allows for superior DNA repair thus preventing cell damage and death. Prompt DNA repair also leads to downstream benefits, because DNA damage is a signal for other cascades such as local immunosuppression. 

Of note, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are similar structures that show excellent promise for their ability to increase coenzyme NAD+. Currently, human clinical trials for photoprotection and skin cancer study niacinamide specifically, so this is the form included in this blend.

Clinical Features

  • Oral NAM reduces the incidence of keratinocyte cancers (including squamous cell and basal cell carcinomas) and actinic keratoses among high-risk immunocompetent patients(1). Studies with immunocompromised transplant patients suggested benefit but failed to reach statistical significance(2). It may be less effective in immunosuppressed patients because the mechanism of action is preservation of skin immunity (which requires immune competence).
  • Oral NAM improves skin hydration by preventing transepidermal water loss(3).
  • Topical NAM: Niacinamide 0.2% and 5% applied after exposure protected from longwave UVA, UVB, and solar-stimulated UV-induced immunosuppression(4). 
  • Topical and oral niacinamide prevents UV-induced immune suppression and tumor formation in mice (5, 6).

Dosing

  • Oral 500mg twice a day for high-risk patients: Most clinicians base recommendations for high-risk skin cancer patients based on the ONTRAC (1) study results for immunocompetent people. We elected to include 250mg as a starting point which can be supplemented with additional NAM for high-risk patients.
  • Protection from immunosuppression is seen in humans at doses of 500mg daily and 1500mg daily(7).
  • Topically, 5% concentration is most commonly used in studies(8). It is available 5%-20% over the counter.

Safety

  • No major adverse effects are reported, even at higher doses in the grams range.
    • 2015 ONTRAC trial: used 500mg twice a day in high risk elderly population for 12 months. Niacinamide was tolerated well without increase in adverse events. There was no significant difference between the study groups with respect to changes in weight, blood pressure, hemoglobin, white cell count, platelet count, or levels of creatinine, alkaline phosphatase, y-glutamyl transferase, alanine aminotransferase or aspartate aminotransferase measured at baseline and at 12 months.
  • A meta-analysis published in Nature Medicine(9) stirred some concern for high-dose niacinamide. It demonstrated that a metabolite of niacinamide (elevated in those with a genetic variant) is associated with an increased risk of cardiovascular disease. The authors proposed that this increase in risk might be offsetting the decrease in risk conferred by an increase in HDL known to result from niacin supplementation. More studies need to be done to determine if the population with this genetic variant should abstain from niacin, but this study does not offset the decades of research we have that does not show increase risk of cardiovascular disease with even high dose niacin/niacinamide. For e.g.
    • Gale et al’s RCT (10): Doses between 1500 and 3000 mg/d was administered for 5 years looking at diabetes outcomes in 522 patients high risk for DM1. No difference between niacinamide and placebo group with regard to side effects.
    • A meta-analysis published by JAMA network open in 2019 included over 17,000 individuals who received niacin and there was no reported increase in cardiovascular disease (11).
  • Renal Disease: For NAM specifically, there appears to be a dose-dependent association between NAM and risk of thrombocytopenia and diarrhea in patients with renal impairment. There has been no report of thrombocytopenia in patients without ESRD.
  • Liver Disease: Elevated liver enzymes have been reported with extended release niacin. For NAM, hepatotoxicity has been documented in a case study of NAM administration of >9 g per day and in other reports of doses greater than 3 g daily(12).
  • Pediatric population: oral niacin has been studied in the pediatric population for children on hemodialysis. Doses in the range of 100-300mg daily are used and the only side effects included nausea, diarrhea, and flushing. People on hemodialysis have a known higher risk of side effects presumably due to the reliance of niacin on renal clearance(13).

Mechanism of Action:

  • Enhances the repair of ultraviolet (UV) radiation-induced DNA damage by mitigating UV-induced energy crisis (3).
  • Reduces the cutaneous immunosuppressive effects of UV radiation via upregulation of succinic dehydrogenase, an essential enzyme in cellular respiration, and tumor suppressor protein p53 (4).
2

Green tea extract

Background

Green tea extracts derived from Camellia sinensis are abundant in flavonoids called catechins. The four major catechin compounds are (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and (−)-epicatechin (EC). EGCG is the most abundant and extensively studied catechin, and green tea metabolites are known to be bioavailable in the dermis and epidermis of the skin. In vivo human studies and animal models demonstrate green tea catechin’s anti-inflammatory, antioxidant, photo-protective, and chemo-preventative effects after topical application and/or oral ingestion (1).

Clinical Features

  • Regular catechin supplementation as low as 540mg per day was found to strengthen the skin’s tolerance against UV radiation induced skin damage (DNA damage) and erythema (increase in MED)  in a systematic review and meta-analysis published by Kapoor et al. in 2021.
  • Intake of 1402 mg of green tea catechins improves skin structural characteristics such as elasticity, roughness, scaling, density and water balance in women (2).
  • Oral administration of green tea polyphenols in mice protects against UV induced non-melanoma skin cancer in terms of tumor incidence and size (3).

Dosing

  • ECGC 250-300 mg daily in supplement form

Safety

  • Daily intakes equal to or above 800 mg of EGCG per day may increase transaminases according to 2018 European Food Safety Authority (EFSA)(4). 
  • In a systematic review in 2018, Hu et al.(5) concluded 
    • Up to 704 mg EGCG/day could be considered a safe level of intake for GTEs consumed in beverage form.
    • When taken as a supplement, up to 338 mg EGCG/day is considered a safe level of intake. 
  • National Center for Complementary and Integrative Health (NCCIH) at the National Institute of Health (NIH) notes that it is safe to consume up to 8 cups of green tea daily (6).
  • Primary concern is for hepatotoxicity at levels >800mg EGCG daily. Use caution in patients with severe liver disease.
  • EGCG may interact with the following medications:
    • Nadolol: Nadolol is a beta-blocker that treats high blood pressure and heart problems. Drinking significant amounts of green tea or high doses of EGCG may reduce the effectiveness of nadolol (6).
    • Lipitor (atorvastatin): Lipitor lowers LDL cholesterol and triglycerides in circulation. EGCG supplements may reduce the absorption and effectiveness of Lipitor (7).

Mechanism of Action

  • Anti-inflammatory: selective inhibition of COX-2 and reduces EGFR pathway (1).
  • Induces rapid repair of DNA. The DNA repair by GTPs is mediated through the induction of interleukin (IL)-12 which has been shown to have DNA repair ability (8).
7

Lutein

Background

Lutein is a carotenoid known primarily for its role in eye health, particularly in protecting against age-related macular degeneration. However, its benefits extend beyond eye health to applications in dermatology and skincare.

Lutein is a naturally occurring pigment found in various fruits and vegetables, particularly in green leafy vegetables like spinach and kale, as well as in egg yolks. It belongs to the family of carotenoids, which are potent antioxidants known for their ability to neutralize free radicals and protect cells from oxidative stress.

Clinical Features

  1. Antioxidant Protection: Lutein is an antioxidant in the skin, scavenging free radicals generated by UV radiation and environmental pollutants. This antioxidant activity helps protect skin cells from oxidative damage, which can lead to premature aging and skin cancer (1,2).
  2. Blue Light Protection: Blue light triggers melasma and other hyperpigmentation in the skin. The importance of protection from blue light and electronic “light pollution” for skin aesthetics is being increasingly recognized. Lutein is able to absorb, and thus filter out, high-energy blue light. Its absorption peak is in the blue wavelengths of visible light with a maximum absorbance at 446nm. It is also important to note that visible light is responsible for one-third of the free radical formation in the skin after full spectrum irradiation and protection from visible light is therefore an essential piece of a comprehensive skin protection plan.
  3. Skin Hydration: Some studies suggest that lutein supplementation may improve skin hydration and elasticity, possibly due to its antioxidant properties and ability to support skin barrier function (3).
  4. Anti-Inflammatory Effects: Lutein exhibits anti-inflammatory properties that can help mitigate skin inflammation and redness, making it potentially beneficial for conditions like acne and rosacea (4).

Dosing

  • Studies investigating the effects of lutein on skin health typically use doses ranging from 5 mg to 20 mg per day.
  • For example, a study evaluating the effects of lutein on skin hydration and elasticity used a daily dose of 10 mg (3).

Safety

  • Digestive Issues: In some cases, high doses of lutein (typically above 20 mg per day) may cause mild gastrointestinal disturbances such as nausea, diarrhea, or stomach cramps.
  • Carotenoderma/Skin Discoloration: High doses of carotenoids can lead to reversible yellowing of the skin known as carotenodermia. This is more commonly associated with high doses of beta-carotene (20-50mg/day), another carotenoid, but may occur with lutein as well in very high doses.
  • Interactions with Medications: Lutein supplements could potentially interact with medications, particularly those that affect blood clotting or blood thinners. However, specific interactions with lutein are not well-documented compared to other supplements.
8

Lycopene

Background

Lycopene is a powerful antioxidant belonging to the carotenoid family, primarily found in tomatoes and other red fruits and vegetables. As a micronutrient, lycopene is absorbed in the gut and deposited into light-exposed tissues where it serves to filter light, scavenge free radicals, and neutralize reactive oxygen species (ROS). 

Clinical Features

  • Lycopene ingestion over 10-12 weeks has been shown to increase minimal erythemal dose (MED) in human clinical trials (1,2). In animal models, it can significantly slow the onset and reduce the incidence, multiplicity, and tumor weights of UVB-induced skin tumors in mice (3).
  • Anti-aging: The extended system of conjugated double bonds endows carotenoids like lycopene with powerful antioxidant properties. They are particularly efficient natural scavengers of singlet molecular oxygen. Lycopene was shown to completely inhibit UVA/B induced upregulation of HO1, ICAM1 and MMP1 mRNA in a 2017 study with lycopene-rich tomato paste (4). Protection from UV-induced oxidative stress and preservation of structural extracellular matrix components like collagen protects from premature skin aging.

Dosing

  • Studies investigating the effects of lycopene on skin health include dosing in the range of 8 mg to 16 mg per day.
  • Human clinical trials demonstrate an increase in minimal erythemal dose after 15mg daily and the equivalent of 16mg/d from tomato paste (2,5).

Safety

  • No upper limit of lycopene has been reported in toxicology studies, and both diet and supplements are safe and well-tolerated at doses up to 3000mg per day (6).
  • Lycopenemia was the only condition reported due to exorbitant lycopene intake via consuming up to 2L of tomato juice. 
  • Medication Interactions: Lycopene may have antiplatelet effects and could potentially interact with anticoagulant medications, increasing the risk of bleeding.
6

Astaxanthin

Background

Astaxanthin (ASX) is a ketocarotenoid most commonly isolated from the microalgae Haematococcus pluvialis. It has gained attention for its benefits in dermatology and skincare. It is found primarily in marine organisms such as microalgae, salmon, shrimp, and krill, where it serves as a protective agent against oxidative stress. ASX is considered to be one of the most effective carotenoids and has been reported to be approximately 10 times more potent as an antioxidant than beta-carotene, 500 times more potent than alpha-tocopherol, and 6000 times stronger than vitamin C (1). 

In dermatology, astaxanthin is valued for its ability to scavenge free radicals and reduce oxidative damage induced by ultraviolet (UV) radiation and other environmental stressors. UV radiation, in particular, is a major cause of skin aging, inflammation, and DNA damage, leading to wrinkles, pigmentation, and skin cancer.

Clinical Features

  • Increases minimal erythemal dose (reduced burning) and preserves hydration of the skin following ultraviolet exposure in humans (2). 
  • Restores moisture content and improves elasticity in human skin (3).
  • In mice, astaxanthin protects against UV-induced photoaging. It reduces UV light-induced wrinkle formation and skin thickening, and it increases collagen (4).

Dosing

Oral supplementation doses range from 2 mg to 12 mg daily for skin health benefits, though some studies have used higher doses up to 16 mg or more per day. There is no universally established maximum dose for astaxanthin, but studies have used doses up to 12 mg to 16 mg daily for several months and much higher doses as a single dose.

Safety

Astaxanthin has been studied extensively for its safety profile, and there are no significant documented adverse effects at standard doses (5, 6). 

Mechanism of Action

  • Antioxidant Protection: Astaxanthin is a potent antioxidant that neutralizes singlet oxygen radicals in the epidermis and dermis generated by UV radiation and environmental stressors (7). Astaxanthin also upregulates endogenous antioxidant enzymes such as superoxide dismutase 2, catalase, and glutathione peroxidase 1 for further sequestration of oxidative stress in UV-irradiated cells (3).
  • Anti-Inflammatory Effects: Its amphipathic structure allows ASX to be incorporated into the bilayers of cell membranes where it reduces lipid peroxidation. Supplementation in humans has been shown to lower concentrations of the plasma inflammatory marker CRP and reduce UV-induced inflammatory mediators in HaCaT keratinocytes and fibroblasts (8). In human photoaged skin, supplementation with ATX combined with collagen hydrolysate resulted in increased expression of procollagen type I mRNA and decreased expression of MMP-1 mRNA (9).
  • Skin Barrier Function: Chalyk et al. demonstrated systemic antioxidant and skin barrier benefits of astaxanthin in humans (10). In mice, astaxanthin is found to reduce transepidermal water loss and promote production of natural moisturizing factors through stimulation of filaggrin proteolysis (11, 12).
4

Pine bark extract

Background

Pine bark extract has gained attention in dermatology due to its antioxidant and anti-inflammatory properties. Pine bark extract contains a variety of bioactive compounds, including flavonoids, catechins, and procyanidins, which contribute to its therapeutic effects. It has been studied for its potential benefits in promoting skin health, protecting against UV-induced damage, and improving various dermatological conditions.

Clinical Features

  • Antioxidant properties protect skin cells from damage caused by UV radiation, pollution, and other environmental factors (1,2).
  • Anti-aging: Pine bark extract has been shown to protect from photoaging in human facial skin with beneficial effects on skin elasticity, smoothness, and hydration corresponding with increased gene expression of collagen type I and hyaluronic acid synthase (3,4,5,6). 
  • UV Protection: Human studies demonstrate an increase in minimal erythemal dose (MED) with follow up keratinocyte cell line studies showing an inhibition of UVR induced NFkB dependent gene expression as a probable mechanism (4).  
  • UV Protection: In mice, oral pine bark extract protected against UV-induced skin cancer (significant number of animals without tumors and reduction in tumor burden in animals bearing tumors) (7).
  • Improvement in melasma (8,9)
  • Improvement in psoriasis (10)

Dosing

  • Studies investigating the effects of pine bark extract on skin health typically use doses ranging from 50 mg to 250 mg per day. Often 1mg/kg.

Safety

  • Human clinical trials do not report significant adverse effects, and pine bark extract is well-tolerated even at higher doses. Minor side effects include mild gastrointestinal symptoms and are transient (3,8,10).

Mechanism of Action

  • Antioxidant Activity: Pine bark extract is a potent antioxidant that scavenges free radicals and reduces oxidative stress in the skin. Shown to increase production of hyaluronic acid synthase and collagen and reduce production of elastase, collagenase and MMPs (1).
  • Anti-inflammatory Properties: Pine bark extract exhibits anti-inflammatory effects by inhibiting key inflammatory pathways in particular NFkB and results in reduction in inflammatory mediators such as TNF-a, 5-LOX and COX-2 (1,4).
3

Grape seed extract

Background

Grape seed extract (GSE) is derived from the seeds of grapes (Vitis vinifera) and is known for its rich content of antioxidants, primarily proanthocyanidins (oligomeric proanthocyanidins or OPCs), flavonoids, and polyphenols. The most abundant phenolic compounds isolated from grape seed are catechins, epicatechin, and procyanidins (1). These compounds are believed to contribute to various health benefits, including potential applications in dermatology and skincare.

Clinical Features

  • UV Protection: Human keratinocyte cell lines treated with proanthocyanidins and grape seed extract show protection from UVB by suppressing oxidant stress, acute inflammation, and cell apoptosis via regulation of MAPK and NF-kB pathways (1,2).
  • UV Protection: Mice supplemented with oral proanthocyanidins demonstrated reduction of UVR-induced skin cancer (3,4).
  • Improved skin hydration and reduced pigmentation (5).

Dosing:

  • Typical doses used in studies range from 100 mg to 400 mg per day.
  • Higher doses, up to 600 mg per day, have been used in some clinical trials without significant adverse effects reported.

Safety:

  • A study assessed the acute toxicity of grape seed extract in rats and found no significant adverse effects even at high doses, suggesting a wide margin of safety (6,7).
  • Human studies have also supported the safety profile of grape seed extract at doses as high as 2500 mg daily. No significant drug interactions have been identified (8).

Mechanism of Action:

  • Antioxidant Properties: GSE contains potent antioxidants that scavenge free radicals and reduce oxidative stress in the skin caused by environmental factors such as UV radiation and pollution. Additionally they enhance CAT, SOD, GSH, and GSH-Px activities (9).
  • Anti Inflammatory Properties: Oligomeric proanthocyanidins protect against UVB induced damage not only by reduction of intracellular ROS but also by anti-inflammatory effects by regulating MAPK and NF-kB signaling pathways (10,11).