Despite our best efforts as dermatologists to encourage sun protection, the incidence of skin cancer continues to rise in the US. In addition, there is an insatiable desire by consumers to prevent the signs of skin aging, including fine lines and wrinkles, mottled pigmentation, and brown spots. Studies demonstrating that sunscreen ingredients can be absorbed into the bloodstream, combined with concerns that they may have an impact on marine life, have made some consumers hesitant about the use of traditional sunscreens. In addition, while exposure to solar radiation is a major contributing factor in determining how skin ages, other environmental factors, such as pollution and cigarette smoke, are also important contributors.¹ It is the combined effect of these environmental factors that ultimately determines the phenotype of extrinsically aged skin. In this regard, sunscreen alone cannot be our only recommendation for protecting skin against environmental aggressors. The use of what is referred to as active protectors such as antioxidants and metal chelators should be considered part of a more comprehensive protection strategy.

Skin Aging and Carcinogenesis

Our understanding of the pathogenesis of skin aging and carcinogenesis continues to evolve. Recent studies have demonstrated that exposure to UV light and even longer wavelengths, such as visible light and infrared, can produce deleterious effects on the skin. Collectively, these wavelengths upregulate reactive oxygen species (ROS) within skin. ROS are normally kept in check by intrinsic antioxidants, but excessive amounts can overwhelm the intrinsic antioxidant system, triggering oxidative stress. Exposure to pollution and other environmental factors such as cigarette smoke also trigger ROS, further contributing to oxidative stress. ROS can damage DNA, proteins, and lipids directly or act indirectly through downstream pathways. Oxidative stress upregulates redox sensitive transcription factors such as activator protein 1 (AP-1) and nuclear factor kappa beta (Nf-kB). AP-1 increases synthesis of matrix degrading metalloproteinases, and Nf-kB increases inflammatory mediators and cyokines. Together, these transcription factors contribute to inflammaging.

While UV directly mutates DNA, ROS also cause DNA damage through oxidation of guanine to 8-hydroxy-deoxyguanine (8-OH-DG) thus contributing to carcinogenesis. It is also of interest that both UVA and pollution cause the release of iron from iron binding proteins increasing intracellular free iron or labile iron.² This labile iron can be used as a catalyzing agent in Fenton’s reaction, further generating ROS and exacerbating oxidative stress.

Strategies for Skin Protection

Effective strategies to protect skin against oxidative stress will improve skin health and appearance. Topical antioxidants have been studied extensively and can be used to augment skin’s defense against UV, VL, and IR. Early studies demonstrated that combination antioxidants (AOXs), such as vitamin C, E, and ferulic acid confer a greater degree of photoprotection against ultraviolet light when compared to single antioxidants alone. They provide greater protection against sunburn and against the formation of sunburn cells, thymine dimers, and P53 upregulation that is seen following UV exposure.³ The combination of C,E, and ferulic acid also reduced UV-induced cytokine mRNA expression. More recently, sunscreen enriched with a combination of AOXs including licochalcone A was shown to reduce VL-induced pigmentation, while sunscreen alone was not effective.⁴ Antioxidants have also been demonstrated to be effective in protecting against IR exposure. The efficacy of an SPF 30 sunscreen alone was compared with the same sunscreen containing an AOX mixture of vitamin C, E, ubiquinone, and grape seed extract for protecting against IRA induced upregulation of MMP-1.⁵ The sunscreen with AOXs reduced the upregulation of MMP-1 mRNA expression seen after IR exposure while the sunscreen alone did not provide significant protection. In addition, combination antioxidants have also been shown to protect skin against pollutant induced oxidative stress and skin damage. Thus, antioxidants should now be part of our treatment armamentarium for protecting against extrinsic skin aging.

The use of topical chelating agents in cosmetic formulations is a novel approach for skin protection that is gaining favor. Chelating agents can bind metals such as iron, preventing it from being used in Fenton’s reaction to generate ROS. Recent studies demonstrate that antioxidants and chelating agents work synergistically to protect skin from photodamage and pollutants.6 Topical deferoxamine (DFO), a potent iron chelator and antioxidant, was studied on human skin explants for its ability to protect against diesel engine exhaust (DEE)-induced changes. DFO alone and in combination with vitamin C, E and ferulic acid counteracted DEE-induced lipid peroxidation, MMP-9 activation, and loss of involucrin and filaggrin. The combination of AOXs and DFO prevented cutaneous damage in an additive manner. Other antioxidants with chelating capabilities include polyphenols, such as green tea catechins, flavonoids, and baicalin.⁷ These naturals have great potential as bimodal active protective ingredients capable of modulating redox and iron homeostasis. Further studies are warranted to determine the benefits of topical chelating agents.

Drs. Farris and Lain are co-founders of the Science of Skincare Summit, to be held October 28-30 in Austin, TX. For information: scienceofskincaresummit.com

1. McDaniel, D.; Farris, P.; Valacchi, G. Atmospheric skin aging-Contributors and inhibitors. J. Cosmet. Dermatol. 2018, 17, 124–137. https://doi.org/10.1111/jocd.12518.

2. Farris PK, Valacchi G. Ultraviolet light protection: Is it really enough? Antioxidants (Basel) 2022 Aug; 11(8): 1484. Published online 2022 Jul 29. doi: 10.3390/antiox11081484 PMCID: PMC9405175

3. Murray, J.C.; Burch, J.A.; Streilein, R.D.; Iannacchione, M.A.; Hall, R.P.; Pinnell, S.R. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J. Am. Acad. Dermatol. 2008, 59, 418–425. https://doi.org/10.1016/j.jaad.2008.05.004.

4. Lim H, Kohli I, Rubolo E, Kolbe L, Hamzavi I. Impact of visible light on skin health: The role of antioxidants and free radical quenchers in skin protection. J Am Acad Dermatol. 2022, 86(3), S27-S37.

5. Grether-Beck, S.; Marini, A.; Jaenicke, T.; Krutmann, J. Effective photoprotection of human skin against infrared A radiation: Results from a vehicle controlled, randomized, double-blind study. Photochem. Photobiol. 2015, 91, 248–250.

6. Pambianchi, E.; Ferrara, F.; Pecorelli, A.; Benedusi, M.; Choudhary, H.; Therrien, J.-P.; Valacchi, G. Deferoxamine Treatment Improves Antioxidant Cosmeceutical Formulation Protection against Cutaneous Diesel Engine Exhaust Exposure. Antioxidants 2021, 10, 1928–1944. https://doi.org/10.3390/antiox10121928.

7. Pourzand, C.; Albieri-Borges, A.; Raczek, N. Shedding a new light on skin aging, iron and redox-homeostasis and emerging natural antioxidants. Antioxidants 2022, 11, 471-507.