Integrative Approach to Sun Protection: Beyond Sunscreen

Protecting skin from photoaging and photocarcinogenesis requires not only sunscreen — ideally a mineral sunscreen with iron oxide — but also use of topical antioxidants, including polyphenols, and consideration of niacinamide and DNA repair enzymes, according to dermatologists who spoke at the annual Integrative Dermatology Symposium.

“We used to talk about protection using UV [ultraviolet] filters, but obviously we need far more than that,” said Patricia Farris, MD, clinical associate professor of dermatology at Tulane University, New Orleans, during a presentation on cosmeceuticals.

While the focus of sunscreens is blocking or absorbing UV radiation and reducing erythema, discoveries on the complex effects of UV radiation on the skin reveal numerous other areas for intervention, said Katie Varman, MD, a dermatologist in Lincoln, California.

“We don’t think enough, for instance, about the immunosuppressive effects of sunlight on the skin,” Varman said during a presentation on topical approaches to sun protection at the meeting. “DNA damage [caused directly by UVB radiation and indirectly by UVA radiation] is a big trigger for local immunosuppression…You put on your sunscreen, and you think you’re protecting your skin, but you really can be getting quite a bit of local immunosuppression.”

UVA radiation causes oxidative stress deeper in the dermis, she emphasized, “which is really important for photocarcinogenesis as well as aging because it causes indirect DNA damage and activation of inflammatory pathways and prevents genetic repair mechanisms from being effective.” Longwave UVA is poorly filtered by most sunscreens, she and Farris emphasized.

Of the array of available photoprotective ingredients, antioxidants’ role in photoprotection is the one most richly documented in the literature. But other agents are currently backed by evidence as well. “The DNA repair enzymes are very expensive, which excludes some people from being able to include these in their regimen,” Varman said in an interview after the meeting. “But I’m surprised they’re not as well known, given the evidence for their benefit.”

Varman and Farris shared the following key points with examples of supporting evidence. (Both dermatologists had disclosures related to the nutraceutical/cosmeceutical industry; Varman owns a nutraceutical company and Farris serves as a consultant to numerous cosmeceutical companies.) 

Antioxidants Lead the Way

Vitamin C is the most commonly used antioxidant in skin care products, and of all the vitamin C derivatives, L-ascorbic acid and tetrahexyldecyl ascorbate are utilized most often, Farris said. Topical vitamin C not only protects the skin by quelching reactive oxygen species and regenerating oxidized vitamin E but also repairs photodamage “because it’s a cofactor for the enzymes that crosslink collagen…and it’s a very effective tyrosinase inhibitor, so it downregulates pigmentation,” she said.

The late Sheldon Pinnell, MD, a dermatologist and physician scientist at Duke University, Durham, North Carolina, “taught us that well-formulated, stabilized forms of vitamin C [such as L-ascorbic acid and vitamin E stabilized with ferulic acid] are effective topically,” she said, helping to neutralize UV-induced free-radical damage in a way that sunscreens do not, protecting the skin against photoaging. His foundational research also demonstrated a mitigation of “some of the photoproducts that we know are associated with carcinogenesis,” Farris said, such as thymine dimer mutations and 8-oxoguanine.

In her presentation, Varman pointed to another Pinnell study of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin as emblematic of the published research on acute UV protection. Ten people were randomized and treated with the mixture or vehicle on the back for 4 days, then exposed to increasing doses of solar-stimulated UV radiation, up to five times of each person’s minimal erythema dose (MED). On day 5, punch biopsies were taken from 5x MED sites and control sites.

Results showed attenuation by the antioxidant mixture of UV-induced generation of sunburn cells, thymine dimers, matrix metalloproteinase-9 expression, and p53-positive cells — each of which has been associated with photocarcinogenesis and photoaging. Pretreatment with the mixture also blocked the suppression of CD1a-expressing Langerhans cells, “which is suggestive of protection against photo-immunosuppression,” Varman said.

Pinnell’s studies are among many that document protection with antioxidants against acute UV radiation (UVR) exposure with respect to changes known to contribute to carcinogenesis and to the wrinkles, laxity, and volume loss of photoaging, Varman said. Largely lacking in the literature are studies investigating the long-term benefit in humans — protection against actinic keratosis (AK) and skin cancer — but “there is no paucity of evidence in animal models,” she said. “There are plenty of murine models that demonstrate this kind of chronic prevention.”

Antioxidants protect against negative effects of visible light and infrared light in addition to UVA and UVB, which “as we now understand, all contribute to photoaged skin,” said Farris, noting that in her opinion, one should “apply antioxidants alone, followed by sunscreen.” In addition, more recent research suggests that topical vitamin C compounds may also protect against ozone-induced degradation of collagen III.

Polyphenols as Antioxidants and More

Polyphenols not only serve as antioxidants but also have been shown to increase levels of endogenous antioxidants (through upregulation of the Nrf2 pathway), serve as anti-inflammatory agents, chelate metals, inhibit glycation, and more, Farris said. These botanical antioxidants “are incredible multi-tasking ingredients for cosmeceuticals and are extremely popular in formulations,” she said.

An industry-sponsored study comparing a serum of 19 water-soluble, enzymatic, and lipid-soluble antioxidants — many of them polyphenols — with a leading vitamin C-vitamin E-ferulic acid formulation found even more significant neutralization of UV-induced oxidative stress with the polyphenol-containing serum than with the vitamin C product, Farris said.

Polyphenols have also been shown to protect against DNA damage and apoptosis, playing a role in chemoprevention, Varman said. Two polyphenols — polypodium leucotomos (PLE) and green tea extract — “really stand out from the rest” in terms of supportive literature regarding photoprotection when used topically, she said.

PLE, which comes from a fern grown in Central and South America, “has been studied topically and orally pretty extensively,” in in-vivo human and murine models, Varman said, and is commercially available in both forms. An oral formulation has been shown to increase MED in humans. 

Much of the published research on topical PLE, she said, has compared sunscreens with and without PLE and suggested that PLE provides added protection against not only erythema (including MED) but also permanent pigment darkening, immunosuppression, and DNA damage as shown through a reduction in cyclobutane pyrimidine dimer production.

One randomized controlled trial published in 2023, Varman noted, engaged 131 participants with severe photoaging and a history of at least three AKs. Those who were randomized to use a topical sun protection factor (SPF) 100+ gel containing PLE over the course of a year had decreased clinical AK and field cancerization parameters, including the number of new lesions and a reduced need for interventions, compared with those who used sunscreen alone. Improvements were even greater in participants randomized to use both topical and oral PLE.

Green tea catechins (a type of polyphenol) — the most abundant and extensively studied of which is epigallocatechin gallate — can be stabilized into topical formulations that have been shown to have anti-inflammatory effects, enable DNA repair, and reduce epidermal Langerhans cell depletion, Varman said.

Human studies have shown that topical green tea extract can reduce erythema, sunburn cells, and DNA damage after UV radiation, and in mouse models, topical green tea extract has been shown to protect against chronic UV-induced nonmelanoma skin cancer, Varman said.

In one such human study, she said, the application of green tea polyphenols applied 30 minutes prior to a 2-MED dose of solar simulated radiation resulted in a dose-dependent reduction in erythema in addition to a reduction in sunburn cells, DNA damage, and UV damage of Langerhans cells.

DNA Repair Enzymes: Illustrative Studies

Marketed in cosmeceuticals and added to some sunscreens, these enzymes are especially important “for your patients with skin cancer or at high risk for skin cancer because they help repair the DNA damage that occurs following UV light exposure,” Farris said.

They are encapsulated in liposomes and absorbed in the epidermis within 1 hour, she said, referring to a 2019 review of DNA repair enzymes and their efficacy. There are three primary types: Photolyase, a light activated enzyme from bacterial and plant sources; endonuclease from the UV resistant microbe Micrococcus luteus; and 8-oxoguanine glycosylase from the mustard plant Arabidopsis thaliana.

As with polyphenols, most published studies of photoprotection with DNA repair enzymes compare sunscreen with and without the enzymes, Varman said.

For example, one study randomized 28 patients with AK to topically apply sunscreens (SPF 50+) with DNA repair enzymes (1% photolyase and 1% endonuclease) or sunscreen alone for 6 months. Hyperkeratosis, one of three main outcomes, was significantly and similarly reduced by both regimens at 6 months. Field cancerization was also significantly reduced by both, but with a more pronounced decrease in the enzyme group. And cyclobutane pyrimidine dimers (CPDs) in skin biopsies — regarded as a UVR-associated molecular signature — decreased more significantly from baseline in the enzyme group than in the sunscreen alone group (a 61% decrease vs 35%, P less than .001).

In another illustrative study looking at acute rather than chronic exposure, 10 people were exposed to solar-simulated UVR at 3x MED for 4 consecutive days. A half-hour prior to each exposure, a SPF 50 sunscreen with photolyase and sunscreen alone were applied to different sites. With skin biopsies taken 72 hours after the last irradiation, researchers measured CPD amounts and the extent of apoptotic cell death.

The sunscreen with the enzyme was superior in reducing both the formation of CPDs and apoptosis (both P less than .001), with a “pretty dramatic” reduction of 93% in CPD compared with 62% with sunscreen alone, Varman said.

Other small trials, including a 2010 study of 17 patients and a 2017 randomized double-blind study of 15 patients demonstrated reductions in AK with topical DNA repair enzymes. Researchers have also shown reduction of new AKs and a reduction in new basal cell carcinomas in a randomized study of 30 patients with xeroderma pigmentosum with topically applied DNA repair enzymes, Varman noted.

Niacinamide for Immunosuppression

Niacinamide got attention when the ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) trial results were published in 2015 in The New England Journal of Medicine. The phase 3 randomized controlled trial of oral niacinamide (500 mg twice or placebo twice a day for 12 months) showed reductions in new nonmelanoma skin cancers and AK in high-risk patients. “Clinically, the difference was small, but it was statistically significant,” Varman said.

When it comes to topical use of niacinamide, a form of vitamin B3, there are not yet any clinical trials demonstrating a reduction in AK or skin cancer. “But it has been demonstrated pretty clearly that it protects against acute UVR-induced immunosuppression [by] mitigating a UV-induced ‘energy crisis’ and improving DNA repair,” said Varman, referring to a review published in 2019.

Researchers have commonly used a niacinamide 5% topical formulation, she said. In one study, topical niacinamide or its vehicle were applied immediately after solar simulated (UVB + UVA), narrowband UVB, and UVA, and Mantoux testing was performed 48 hours later. Immunosuppression was measured as the difference in Mantoux-induced erythema between unirradiated control sites and test sites, and cell cultures were used to evaluate the modulation of cellular energy metabolism.

“If you put allergens on the skin in the setting of sunlight exposure, you get less of a hypersensitivity response due to immunosuppression. So you can use how large the immune reaction is to the purified protein derivative of the tuberculin (PPD) test to judge how much immunosuppression was caused by the UV exposure,” Varman explained.

The researchers concluded that niacinamide protected against UV-induced immunosuppression from both UVB and UVA (including longwave UVA), and notably, she said, they reported that longwave UVA — which is not well filtered by sunscreens — was “highly immunosuppressive even at doses equivalent to 20 minutes of sun exposure.”

Another study of topical niacinamide, which similarly used the Mantoux reaction as a model of skin immunity and demonstrated protection, found that men were immunosuppressed by solar-simulated UV doses that were three times lower than those required to cause immunosuppression in women, Varman pointed out.

Topical niacinamide “is one of my favorites to support DNA repair as it is one of the few [protective agents] that show benefit when applied after sun exposure,” she said, “although the studies of niacinamide do involve fairly immediate application.”

Practice Pearls and a Word on Sunscreen

In an interview after the meeting, Varman said she commonly advises patients with a history of skin cancer or who are at high risk to take oral niacinamide as well as other oral nutraceuticals such as omega-3 fatty acids, carotenoids, PLE, and green tea extract. For topicals, she usually “breaks things up” for her patients and recommends an antioxidant serum in the morning and topical niacinamide — as well as DNA repair enzymes for patients who are at “highest risk” and are able financially — at night.

In addition, she advises her patients across the board to eat a diet with abundant colorful polyphenols, carotenoids, and omega-3 fatty acids.

Regarding sunscreens, Varman and Farris noted at the meeting that mineral/physical blocker sunscreens, especially those with iron oxide, help protect against visible light as well as UV light. These sunscreens also increase protection against longwave UVA compared with chemical sunscreens, they both said. “Iron oxide is especially important in patients with skin of color because they’re prone to hyperpigmentation,” Farris said at the meeting.

Increasingly, Varman said in the interview, she sees patients seeking out mineral sunscreens because of concerns about systemic absorption of chemical blockers and possible safety issues. Several years ago, she noted at the meeting, following new studies showing rapid systemic absorption of chemical sunscreen ingredients, the US Food and Drug Administration proposed that chemical sunscreens be reclassified as “not GRASE” (not generally recognized as safe and effective) — or GRASE category III.

(More specifically, the FDA’s proposed order proposes “not GRASE” status for sunscreens containing aminobenzoic acid and trolamine salicylate because of known safety issues, and “not GRASE” status for sunscreens containing any of a dozen other active ingredients because additional data are needed to show these sunscreens are GRASE.) 

“I always recommend to my patients, use the minerals until we have an idea of what [the chemical sunscreens] are doing in our bodies,” Varman said at the meeting, noting that available mineral sunscreens are increasingly less pasty and more cosmetically appealing.

Varman disclosed that she is a scientific advisor for Anirva, a nutraceutical company, and that she owns Shine Nutraceuticals, which is currently launching a skin care supplement that contains antioxidants and other ingredients discussed at the meeting and in this story. Farris disclosed that she has received consulting fees from AlumierMD, LaRoche Posay, CeraVe, Skinceuticals (a company established by Sheldon Pinnell, MD), Pierre Fabre, Sente, OneSkin, and Estée Lauder, and honorarium from Rationale.