American Journal of Clinical Dermatology (2021) 22:819–828

https://doi.org/10.1007/s40257-021-00632-5

REVIEW ARTICLE

Sunscreens and Photoaging: A Review of Current Literature

Accepted: 29 July 2021 / Published online: 13 August 2021

Abstract
Sunscreens have been on the market for many decades as a means of protection against ultraviolet-induced erythema. Over
the years, evidence has also shown their efficacy in the prevention of photoaging, dyspigmentation, DNA damage, and
photocarcinogenesis. In the USA, most broad-spectrum sunscreens provide protection against ultraviolet B (UVB) radia-
tion and short-wavelength ultraviolet A (UVA) radiation. Evidence suggests that visible light and infrared light may play a
role in photoaging and should be considered when choosing a sunscreen. Currently, there is a paucity of US FDA-approved
filters that provide protection against long UVA (> 370 nm) and none against visible light. Additionally, various sunscreen
additives such as antioxidants and photolyases have also been reported to protect against and possibly reverse signs of pho-
toaging. This literature review evaluates the utility of sunscreen in protecting against photoaging and further explores the
requirements for an ideal sunscreen.

1 Introduction
Key Points 
Chronic sun exposure has long been known to cause pho-
The perception of sunscreen use has shifted from purely toaging, a process where the skin undergoes changes in
protecting against ultraviolet (UV)-induced erythema to epidermal thickness, increases in pigment heterogene-
broad-spectrum protection against not only erythema but ity and dermal elastosis, degradation of collagen in the
also photoaging, dyspigmentation, DNA damage, and dermis, development of ectatic vessels, and increases in
photocarcinogenesis. mutagenesis of keratinocytes and melanocytes in the skin
Evidence suggests that visible light and infrared light [1]. Clinically, this is characterized by an increase in rhyt-
may play a role in photoaging and should be considered ides, telangiectasias, dyspigmentation including lentigines
when choosing a sunscreen. A broad-spectrum tinted and ephelides, volume loss, and cutaneous malignancies
sunscreen with sun protection factor (SPF) ≥ 30 used [1]. A recent observational study further characterized skin
daily will offer protection against UV radiation and vis- aging as hypertrophic and atrophic variants, with atrophic
ible light to reduce their effects on photoaging. photoaging presenting with erythema and increased risk of
skin cancers and hypertrophic photoaging with increased
Sunscreen additives such as antioxidants, photolyases, skin thickness and sallowness [2].
and more have not only opened the door to improved In today’s society, the value placed on a youthful
photoprotection against skin aging but also the explora- appearance is reflected in the multibillion-dollar industry
tion of newer theories in the reversal of skin aging, but centered around anti-aging products [3, 4]. It has been
larger-scale and replicable studies are needed before reported that approximately 80% of skin aging on the face
clinical guidelines can be issued. can be attributed to ultraviolet (UV) exposure [5]. There-
fore, despite the emphasis of the market on the reversal of
skin aging, the best defense against cutaneous age-related
changes is through prevention with rigorous photoprotec-
tion [4]. It should be noted that proper photoprotection
* Tasneem F. Mohammad consists of seeking shade when outdoors; wearing a wide-
[email protected] brimmed hat, photoprotective clothing, and sunglasses;
and applying sun protection factor (SPF) ≥ 30 broad-
1
Department of Dermatology, Henry Ford Health Systems, spectrum tinted sunscreen on exposed sites.
Henry Ford Medical Center-New Center One, 3031 W.
Grand Boulevard, Suite 800, Detroit, MI 48202, USA

Vol.:(0123456789)

820 L. L. Guan et al.

In the USA, most broad-spectrum sunscreens provide levels, which are enzymes involved in collagen degradation
protection against UVB radiation and short wavelength [12, 15]. Additionally, repeat exposure to UVA on in vivo
UVA radiation. However, there is a paucity of US FDA- human skin induced elevated markers of photoaging, such
approved filters that provide protection against long UVA as ferritin and lysozyme, which are involved in the oxidative
(> 370 nm) and none against visible light (VL), making stress response and elastin degradation, respectively [16]. In
the ideal sunscreen a product that requires further inno- a study looking at asymmetric UVA exposure of the face,
vation and research. Notable exceptions are pigmentary chronic exposure to UVA significantly affected the clinical
grade zinc oxide and titanium dioxide, which reflect VL; level of wrinkling and roughness of the skin [17]. Further-
however, the whitish discoloration they leave on the sur- more, in a study of 22 participants exposed to multiple ses-
face of the skin makes them cosmetically unappealing to sions of low-dose UVA1, increasing levels of MMP-1 and
consumers. This review evaluates the utility of sunscreen MMP-3 were observed in a dose-dependent response in the
in protecting against photoaging and further explores the dermis, further highlighting the role of UVA in collagen
requirements of an ideal sunscreen. breakdown and photoaging [13]. In skin of color, UVA has
been shown to induce irregular spotty pigmentation associ-
ated with photoaging [12].
However, the effects of UVA and UVB are not always
2 Electromagnetic Radiation distinct, as overlapping cutaneous biologic effects have been
and Photoaging observed. UVA has been shown to induce CPDs through ROS
generated by photo-activation of UVA-absorbing molecules
Solar UV radiation (UVR) consists of UVA (320–400 nm), (chromophores) in the skin such as riboflavin, porphyrins, and
UVB (280–320 nm), and UVC (100–280 nm). UVA is heme-containing proteins [18]. Similarly, UVB has also been
further categorized as UVA1 (340–400 nm) and UVA2 shown to induce dermal fibroblast senescence [19].
(320–340 nm). UVC is the shortest wavelength and con- There is increasing evidence that infrared light (IR; 700
sidered the most damaging type of UVR. However, it is nm–1 mm) and VL (400–700 nm), predominantly in the
completely absorbed by the ozone and does not reach the blue light range (380–455 nm), play a role in photodam-
earth’s surface [6]. age and photoaging. Studies have demonstrated that VL can
UVB is the major portion of UVR that induces sunburns independently generate ROS, proinflammatory cytokines,
or UV-induced erythema. It is known to be significantly and MMP-1 expression and potentiate the effects of UVR
more erythemogenic than UVA [6]. For example, for skin [20–23]. Effects of photoaging have also been observed
phototype I, the minimal erythema dose for UVB is 20–40 with irradiation of skin within the UV/VL boundary region
mJ/cm2, whereas that for UVA is 20–40 J/cm2. Although (385–405 nm), demonstrating differential expression of
UVB accounts for approximately 6% of all UVR that reaches genes involved in inflammation, oxidative stress, and pho-
the earth’s surface, it is more cytotoxic than UVA, causing toaging when compared with nonirradiated skin [24]. Like-
direct DNA damage through photon absorption in the form wise, in vivo skin irradiated with IR and VL has shown
of cyclobutane pyrimidine dimers (CPDs) or 6,4-photoprod- significantly increased MMP-1 and MMP-9 expression and
ucts that eventually induce mutagenesis and skin cancers [7, decreased type I procollagen expression, implicating IR and
8]. UVB has been shown to be highly associated with the VL light in the degradation of dermal collagen [25]. More-
development of squamous cell carcinomas [9]. Addition- over, studies have demonstrated that there is a synergistic
ally, even suberythemal doses of UVB have been shown to relationship between even small amounts of UVA1 and VL
induce CPD formation and therefore increased p53 expres- in the induction of increased and prolonged pigmentation
sion as cells undergo apoptosis or repair [10]. UVB has also [21, 26]. This suggests that VL and IR may play a significant
been shown to induce matrix metalloproteinases (MMPs), but underreported role in photoaging and dyspigmentation.
reactive oxygen species (ROS), and elastases involved in Although the exact mechanisms are not yet fully under-
photoaging [11]. stood, increasing literature indicates a need for photoprotec-
UVB is predominantly absorbed by the skin’s epider- tion against the broad spectrum of electromagnetic radiation
mis, whereas UVA has a longer wavelength and therefore (UV, VL, and IR) to prevent photoaging.
deeper dermal penetration, making it the primary driver of
photoaging [12]. Although UVA is lower in energy than
UVB, it is approximately 20 times more abundant in the 3 Role of Sunscreens in Photoaging
earth’s atmosphere and is not blocked by glass [13]. The
ratio of UVB/UVA varies by season [14]. Studies of UVA The concept of a topical photoprotective product has been
on skin models demonstrated that UVA caused the induc- around since the times of the ancient Egyptians in 4000 BC,
tion of apoptosis in dermal fibroblasts and increased MMP but the first commercial sunscreens were not available until
Sunscreens and Photoaging 821

the 1920–1930s [27, 28]. At that time, understanding of UV There is good evidence that daily photoprotection and
radiation was limited and focused mainly on UVB protec- daily sunscreen use plays an important role in the preven-
tion. With the increasing popularity of sunscreen over the tion of photoaging [37, 38]. In a study of 46 patients ran-
years, the concept of standardization of photoprotection domly selected to use vehicle or sunscreens with UVA and
against UVB was introduced [27]. SPF was recognized by UVB protection daily for 24 months, a significant histologi-
the FDA in 1978 as the standard for measuring sun protec- cal difference in solar elastosis was observed in the vehicle
tion [27]. versus treatment group [38]. Furthermore, in a study of 12
UV-induced erythema is mostly attributed to UVB, with subjects in which each subject was exposed to one minimal
a minor contribution by UVA2. The concept of SPF, an erythemal dose of simulated solar radiation to three areas
assessment using UV-induced erythema as an endpoint, as of buttock skin (unprotected skin, vehicle, and day cream
a sole measurement of sun protection persisted for many with UVA and UVB protection) and control (no exposure),
decades despite advances in the study of UVR suggesting the unprotected skin demonstrated significant melanization,
that UVA may play a significant role in photoaging [27, 29, increased stratum corneum and stratum granulosum thick-
30]. In 1992, the UVA star rating system was created by The ness, elevated expression of tenascin, reduced type I procol-
Boots Company in the UK but was not widely implemented lagen, and slightly increased lysozyme and alpha-1 antit-
[27]. Although other methods of evaluating the efficacy of rypsin, which were all mitigated by the day cream–sunscreen
UVA filters have been proposed, the FDA currently uses combination [39]. Not only have sunscreens been shown to
critical wavelength (CW) determination. With this method, prevent photoaging but evidence also suggests that they may
sunscreen products whose 90% UV absorbance occurs at play a role in the reversal of extrinsic aging. In a prospective
≥ 370 nm are allowed to be labeled as “broad spectrum” study, 32 subjects were asked to apply daily broad-spectrum
[31]. In Europe, the International Organization Standardiza- photostable sunscreen (SPF 30) for 52 weeks. At the end of
tion 24443 guidelines use a minimum ratio of UVA protec- the study, significant improvements in skin texture, clarity,
tion factor to SPF of 1:3 for all marketed sunscreens [32]. In and mottled and discrete pigmentation were observed, with
a study of 20 sunscreens tested against the FDA guidelines 100% of subjects showing improvement in skin clarity and
and the ISO 24443 guidelines, 19 of 20 sunscreens met the texture [40]. However, further research into the molecular
CW requirements set by the FDA, whereas only 11 of 20 mechanism of sunscreen’s effects on the reversal of chrono-
sunscreens met the ISO 24443 standard [31]. To address logic aging must be performed.
this disparity, the FDA proposed a new rule on sunscreens
in 2019 that specifically highlighted a requirement for a
UVA1 (340–400 nm) to UVA and UVB (290–400 nm) ratio 4 Challenges and Limitations of Current
of ≥ 0.7; however, the FDA has not yet made a final decision Sunscreens
[33]. Clearly, there exists further need for global standardi-
zation to help protect and guide consumers. Sunscreen technology has made great advancements in
In recent years, tinted sunscreens have become more accessibility, consumer acceptability, and overall safety and
prevalent as a means of protection against VL. Most FDA- efficacy over the years. However, the challenges and limita-
approved compounds for UV protection do not adequately tions of current sunscreens leave room for further research
protect against VL because compounds must be opaque to and innovation. In the evaluation of sunscreens available for
filter VL [34]. Zinc oxide and titanium dioxide can protect US consumers today, FDA regulations, safety in humans,
against VL but only when they are pigmentary grade and and safety for the environment must be carefully considered.
not micronized. Tinted sunscreens incorporate combinations In the 2019 proposed rule on sunscreens, the FDA
of iron oxides and pigmentary titanium dioxide to offer VL proposed to categorize sunscreen filters as category
protection and utilize the different colors of iron oxides and I—“GRASE” (Generally Recognized as Safe and Effec-
pigmentary titanium dioxide to improve color match on tive), category II—non GRASE, or category III—requires
people of all Fitzpatrick skin types [34, 35]. It should be further evaluation (Table 1) [41]. Currently, only two UV
noted that iron oxides are not considered to be UV filters so filters are category I: titanium dioxide and zinc oxide [42].
are listed under “inactive ingredients” on sunscreen product Both of these inorganic filters work by scattering, reflecting,
packages, whereas pigmentary-grade titanium dioxide and and absorbing UV. The aggregation of these particles on the
zinc oxide are FDA-approved inorganic filters. However, the skin means they tend to leave a whitish hue on the skin that
exact efficacy of specific tinted sunscreens for VL protection is unacceptable for many consumers, especially those with
has been largely unregulated as no standards or guidelines skin of color [43, 44].
for VL protection yet exist. A method for VL protection fac- In the 2019 FDA-proposed rule, two ingredients, para-
tor has been recently suggested using in vivo assessment in aminobenzoic acid (PABA) and trolamine salicylate,
melano-competent subjects [22, 36]. were classified as category II and banned from products

822 L. L. Guan et al.

marketed in the USA given their safety concerns. PABA absorb the higher energy of UV rays and emit a lower
has been linked to cases of allergic and photoallergic der- thermal energy [41, 45]. It should be noted that the FDA
matitis and is a cross-sensitizer to sulfonamide antibiot- is only requesting safety data for these 12 filters and did
ics, thiazide diuretics, local anesthetics, and dyes [42]. not question the efficacy of UV filters. None of the 12 cat-
Trolamine salicylate is a salicylate class of UV filters and egory III UV filters offer effective visible light protection,
has been linked to systemic absorption and increased risk and only meradimate and avobenzone offer partial UVA1
of bleeding and salicylate toxicity [42]. It should be noted protection [41].
that neither of these has been used in the US market for The organic UV filters can be categorized into cinna-
years, so this categorization does not affect the US market. mates, benzophenones, salicylates, PABA derivatives, and
Organic UV filters, dioxybenzone, sulisobenzone, oxy- others. Octinoxate, a cinnamate, is the most common sun-
benzone, avobenzone, cinoxate, octinoxate, octisalate, screen ingredient in the USA. It is photolabile and is often
homosalate, padimate O, ensulizole, meradimate, and combined with other UVB absorbers to increase both its
octocrylene have now been categorized as category III, final SPF and its photostability [46].
which means that additional data to determine the general The benzophenones include dioxybenzone, sulisoben-
recognition of safety is needed [42]. Organic UV filters zone, oxybenzone, and avobenzone, with oxybenzone the

Table 1  US FDA-approved ultraviolet filters

Inorganic filters
 Titanium dioxide GRASE (I) 25 Dependent on particle size UVB, UVA2, UVA1, visible light
 Zinc oxide GRASE (I) 25 Dependent on particle size UVB, UVA2, UVA1, visible light
Organic filters
 Benzophenones
  Dioxybenzone (benzophenone-8) Non GRASE (III) 3 352 UVB, UVA2
  Oxybenzone (benzophenone-3) Non GRASE (III) 6 288, 325 UVB, UVA2
  Sulisobenzone (benzophenone-4) Non GRASE (III) 10 366 UVB, UVA2
 Cinnamates
  Cinoxate Non GRASE (III) 3 289 UVB
  Octinoxate (octyl methoxycinnamate, Non GRASE (III) 8 311 UVB, UVA2
Parsol MCX)
 Others
  Butyl methoxydibenzoyl methane Non GRASE (III) 3 360 UVA1
(avobenzone, Parsol 1789)
  Ecamsule (terephthalylidene dicamphor No GRASE ­ratingb 3 NA UVA1, UVA2
sulfonic acid)
  Ensulizole (phenylbenzimidazole Non GRASE (III) 4 310 UVB, UVA2
sulfonic acid)
  Meradimate (menthyl anthranilate) Non GRASE (III) 5 340 UVA1, UVA2
  Octocrylene Non GRASE (III) 10 303 UVB, UVA2
 PABA derivatives
  Padimate O (octyl dimethyl PABA) Non GRASE (III) 8 311 UVB
  Para-aminobenzoic acid (PABA) Non GRASE (II) 15 283 UVB
 Salicylates
  Homosalate (homomethyl salicylate) Non GRASE (III) 15 306 UVB, UVA2
  Octisalate (octyl salicylate) Non GRASE (III) 5 307 UVB, UVA2
  Trolamine salicylate (TEA salicylate) Non GRASE (II) 12 260–355 UVB

GRASE generally recognized as safe and effective, NA not applicable, PABA para-aminobenzoic acid, UV ultraviolet
a
 2019 FDA Proposed Rule has suggested three categories: I—GRASE; II—non GRASE; III—insufficient safety data to make a positive GRASE
determination
b
 Approved through new drug application process
Sunscreens and Photoaging 823

most commonly used agent in the group [46]. Although ben- ingredients—oxybenzone and octinoxate—demon-
zophenones have been shown to be effective UVA filters, strated that oxybenzone had no adverse effects on male
their lack of photostability requires them to be compounded and female fertility, female reproductive hormone levels,
with other filters such as octocrylene, salicylates, micronized adiposity, fetal growth, childhood neurodevelopment, or
zinc oxide, and titanium dioxide to improve their photosta- sexual maturation, and octinoxate had no effect on thy-
bility [44, 46, 47]. Additionally, oxybenzone is the most roid and reproductive hormone levels [53]. Although the
common photoallergen of the UV filters. review recommended further research into the effects of
The salicylates octisalate and homosalate are only weak oxybenzone levels on thyroid hormone, testosterone level,
UVB absorbers and are mainly used in sunscreens as pho- kidney function, and pubertal timing, the evidence is not
tostabilizers in combination with other organic filters [46]. yet sufficient to support a causal relationship between
Padimate O is a PABA derivative; like its predecessor, it the elevated systemic levels of oxybenzone or octinoxate
has potent UVB filtration but is rarely used [44, 46]. Ensu- and adverse health outcomes. Further longitudinal ran-
lizole is primarily a UVB filter with minimal UVA2 activity domized controlled studies should be performed before
[48]. Meradimate is a weak UVA blocker and has no activity factoring the biological effects of systemically absorbed
against UVB [41, 46]. Octocrylene is a photostable UVB agents into clinical and practical guidelines [54, 55]. A
and UVA2 filter primarily used as a photostabilizer in con- recent report by Valisure LLC, an independent labora-
junction with other filters [46]. Ecamsule (Mexoryl SX) is tory, also raised safety concerns regarding benzene in
an effective UVA filter that has been shown to be effective sunscreen products. After testing multiple batches of 69
against photoaging when combined with UVB filters [49]. brands of sunscreen and after-sun skincare products, they
It has been approved via the new drug application process, found that 78 batches contained elevated levels of ben-
with its use as an active ingredient permitted only in certain zene, a carcinogen known to cause leukemia and lym-
products under specific concentrations [41, 43, 44]. phoma [56]. It is important to note that both organic and
Although other photostable and more effective broad- inorganic sunscreens and some cosmetic products that
spectrum UV filters, including bemotrizinol, bisoctrizole, did not contain any UV filters were among the contami-
and drometrizole trisiloxane, are available in other coun- nated products. In addition, many sunscreen products
tries, these agents—along with many other UV filters avail- tested did not contain benzene. The report concluded
able in other countries—are still pending FDA approval that the contamination was due to supply chain issues
in the USA [27, 41]. In over a decade, no new UV filters in the manufacturing process rather than degradation of
have been approved by the FDA to be added to the 16 cur- sunscreen filters. These findings led to an FDA citizen
rently approved filters. In contrast, the European Commis- petition for the recall of identified batches of sunscreen
sion currently has 27 approved UV filters [27]. However, with elevated levels of benzene and further investigation
with the Coronavirus Aid, Relief, and Economic Security into these products and their manufacturing processes.
(CARES) Act signed into law in March 2020, the FDA has A full report, including a list of products tested, can be
been mandated to move from a laborious rulemaking process found on the Valisure website [57].
to an administrative order process, which means it should Additionally, the National Oceanic and Atmospheric
not take as long to implement a monograph. The FDA is to Administration identified ten sunscreen ingredients as
issue a new proposed administrative order by 27 September being toxic to coral and marine life: oxybenzone, benzo-
2021. Once the final administrative order has been enacted, phenone-1, benzophenone-8, PABA, 4-methylbenzylidene
industry has 12 months to comply. In addition, the CARES camphor, 3-benzylidene camphor, nano-titanium dioxide,
Act also incentivizes innovation by providing an 18-month nano-zinc oxide, octinoxate, and octocrylene [58]. Studies
exclusivity period to the requesting manufacturer of a new that demonstrated marine toxicity were performed in vitro
filter [50]. with high concentrations of sunscreen ingredients [44, 55,
Controversy regarding organic sunscreen safety in 59]. In a review looking at all 32 published studies until
humans has increasingly been a topic of discussion after June 2020, 14 different organic UV filters in seawater near
studies showed systemic absorption of six commonly coral reefs were detected in the nanograms per liter range,
used sunscreen active ingredients [51, 52]. This 2020 in contrast to toxic levels in the micrograms per liter to
study of 48 randomized participants applying 2 mg/ milligrams per liter range reported in nine papers [60].
cm 2 of sunscreen product to 75% of body surface areas This puts the toxic levels of organic UV filters at 1000-
between one and four times per day for 4 days demon- to 1 million-fold higher concentrations than currently
strated systemic absorption of avobenzone, oxybenzone, reported. Although 27 of the 32 reviewed studies showed
octocrylene, homosalate, octisalate, and octinoxate [51]. no risk of UV filters to coral reefs, three studies of oxyben-
However, a systematic review of 29 studies looking at the zone and octinoxate demonstrated a few data points where
effects of two of the most commonly studied sunscreen some risk was present [54]. This reflects the major data

824 L. L. Guan et al.

gaps that immediately need to be addressed with high- the study was performed ex vivo and may not correlate to
quality monitoring and toxicity studies applicable to the in vivo responses in humans. More recent reviews and
real world. To address this issue, on 9 February 2021, the studies have demonstrated positive effects of the addition
National Academies formed a committee sponsored by the of antioxidants into sunscreen formulations. For example,
Environmental Protection Agency to study the environ- a study looking at skin irradiated with UVB found that
mental and health impacts of sunscreens. Although data sunscreens with SPF 25 and a mixture of caffeine, vita-
supporting that the coral reefs are adversely impacted by min E, vitamin C, Echinacea pallida extract, gorgonian
environmental exposure to UV filters are limited, the state extract, and chamomile essential oil demonstrated less
of Hawaii banned sunscreens containing oxybenzone and MMP-1 expression than those with only SPF 25 [63]. The
octinoxate in 2018, and Key West, Florida, USA, did the variability in the efficacy of antioxidants in sunscreens
same in 2019 [59]. may depend on the formulation of the sunscreen. It has
Although FDA guidelines aim to protect US consumers been proposed that, for antioxidants to be efficacious, they
from harm, it has also greatly diminished the variety of must have high antioxidative capacities, be present in high
UV filters available to consumers. Newer and more effec- concentrations, be stable in the final formulation, and be
tive broad-spectrum UV filters are available in other coun- able to penetrate the stratum corneum and still exist at high
tries but are not currently FDA approved [41]. With the enough concentrations in the epidermis and dermis to be
new proposed administrative order under the CARES Act effective [61].
and careful consideration of human safety, environmental In terms of antioxidants that have been explored in topi-
safety, photostability, and consumer cosmesis, the devel- cal formulations, vitamin C (l-ascorbic acid) is the pre-
opment and approval of new sunscreens that are effective dominant antioxidant in the skin and plays an important
against UVA, UVB, and VL must be considered for protec- role in the skin’s aqueous compartments because of its
tion against photoaging. water solubility [61]. It also helps replenish vitamin E,
acts as a cofactor in collagen synthesis, and reduces elas-
tin accumulation [61]. It is not synthesized by the human
5 Additives in Sunscreens body and must be replenished via oral intake [64]. Addi-
tionally, because of its ionic charge at physiologic pH,
With the rise of cosmeceuticals and additives in sun- it cannot penetrate the stratum corneum without becom-
screens, it is important to evaluate the safety and efficacy ing unstable. Fortunately, a stable formulation can be
of these substances. Although the exact mechanism of made by compounding it with other antioxidants: vitamin
UVR- and VL-induced photoaging is still being explored, E (alpha-tocopherol) and ferulic acid [61, 64]. Murray
the downstream effects of increased ROS, MMPs, and et al. [65] demonstrated that skin irradiated with solar-
DNA damage have been widely reported [8, 11]. To com- simulated UVR after application of a topical formulation
bat the deleterious effects of sunlight on the skin, additives of 15% l-ascorbic acid, 1% alpha-tocopherol, and 0.5%
have been used or proposed in sunscreens to enhance pho- ferulic acid (CEFer) for 4 days significantly decreased UV-
toprotection and help prevent photoaging. induced erythema, sunburn cells, thymine dimers, and p53
Antioxidants play an important role in preventing, ame- induction when compared with untreated skin. Further-
liorating, and dampening free radicals and oxidative stress. more, vitamin E has been shown to be effective in the
Although our bodies produce natural antioxidants, UVR reduction of lipid peroxidation, photoaging, immunosup-
and other stressors can often overwhelm our endogenous pression, and photocarcinogenesis in multiple animal and
supply [61]. Topical antioxidants have been formulated human studies [61]. This suggests a role for topical CEFer
into sunscreens to replenish depleted antioxidant supplies in protecting against photoaging and skin cancers [64, 65].
and diminish oxidative stress on the skin. Yet the exact Vitamin A and its derivatives, mainly retinoids and carot-
role and efficacy of antioxidants in sunscreens remains enoids, have been well studied in the realm of antiaging
controversial. A 2011 ex vivo study by Wang et al. [62] and have shown benefit in the prevention and reversal of
evaluated the radical skin protection factor (RSF) and photoaging [66]. They bind to cytoplasmic receptors such
antioxidant power (AP) of 12 sunscreen products contain- as cellular retinoic acid-binding protein types I and II and
ing vitamin C, vitamin E, or other antioxidant substances cellular retinol-binding protein as well as nuclear receptors
against simulated UVA- and UVB-induced ROS. RSF was such as nuclear retinoic acid receptors and retinoid X recep-
defined as the ratio of free radicals in unprotected skin to tors to inhibit activation of protein-1 and MMP-1 expression
protected skin, and AP evaluates the capacity and reaction [61]. This leads to increased epidermal proliferation, lead-
time of antioxidants by measuring free electron spin [62]. ing to epidermal thickening, compaction of the stratum cor-
They demonstrated that the RSF correlated with the UVA neum, synthesis and deposition of glycosaminoglycans, and
RSF rather than any antioxidant ingredients [62]. However, increased collagen production [61, 67]. Furthermore, there
Sunscreens and Photoaging 825

is evidence that topical retinoids may play a role in chemo- better protected human skin against solar-simulated UVR
prevention of nonmelanoma skin cancers through initiating over sunscreen alone in regards to decreasing MMP-1 [63].
growth arrest of tumor cells and normal cellular differentia- Additionally, green tea extract compounded with resveratrol,
tion [68]. However, given the relative instability of retinol another polyphenol, provided SPF protection independent of
and retinoids when exposed to UV and visible light, their use physical and chemical UV filters, but additional in vivo stud-
as a sunscreen additive is predominantly for their anti-aging ies must be performed to fully assess its effectiveness [76].
effects and not for increased photoprotection. They are rarely Melatonin acts as an antioxidant in three different but
found in recreational sunscreens, and their stability is highly complementary ways. It can act as a free radical scaven-
dependent on their formulation and chemical structure. For ger, decrease free radical generation, and upregulate anti-
example, when tretinoin is compounded in ethanol, it under- oxidant enzymes [77]. It has shown promise against both
goes isomerization within just a few seconds when irradiated UVB- and UVA-induced oxidative stress. In studies of
with light of 300–800 nm [69]. The stability of tretinoin is human melanocytes and keratinocytes, cells pretreated
improved when incorporated into liposomes [69]. Retinyl with melatonin decreased p53 expression, improved DNA
palmitate is an ester of retinol that is widely used in cos- repair, and decreased CPD generation [78, 79]. An in vitro
metic products because of their high thermal stability when study of mouse fibroblast cells (NIH3T3) pretreated with
compared with retinol [70]. A study of 11 healthy volun- melatonin and irradiated with UVA demonstrated increased
teers using two formulations of retinyl palmitate for 60 days heme-degrading enzymes and suppression of UVA-induced
reported significant improvements in skin smoothness, skin photodamage when compared with untreated irradiated cells
roughness, scaliness, and wrinkles with both formulations [77]. Additionally, melatonin protected against UV-induced
[71]. Retinyl palmitate can be compounded with photostabi- erythema and activated endogenous enzymes to act against
lizers and UV filters and loaded onto nanotechnology-based oxidative stress [75]. This suggests a potential role of mela-
drug-delivery systems to improve stability and drug penetra- tonin as an additive to protect keratinocytes, melanocytes,
tion, but large-scale randomized controlled trials are needed and fibroblasts against UV-induced photoaging.
to study the antiaging properties of these formulations [70, Many studies have shown that multicellular algae not
72]. Additionally, concerns have been raised regarding an only have UV-absorbing properties but also provide ben-
increase in cutaneous malignancy with simultaneous use of efits against oxidative stress [75]. Mycosporine-like amino
topical retinyl palmitate and UVR exposure. A recent study acids (MAAs) produced by algae are potent UV filters
looking at SKH-1 hairless mice treated with control cream or with maximum absorption between 310 and 362 nm [80].
creams containing retinyl palmitate and subsequently irradi- Shinorine is a commercialized MAA extracted from a type
ated with simulated solar light demonstrated an increased of red algae, Porphyra umbilicalis, and has already been
risk of photo-co-carcinogenesis in the group using cream used in sunscreens produced by two European compa-
containing retinyl palmitate [73]. However, these claims nies [81]. Furthermore, the algae and algae products have
have not been largely substantiated or reported in humans also demonstrated protective properties against photoag-
and need to be further studied. ing. Alga Corallina pilulifera methanol extract reduced
Other antioxidants that have been reported in the litera- MMP-2 and MMP-9 in UV-irradiated human dermal fibro-
ture include soy extracts, polyphenols, melatonin, algae blasts [82]. Additionally, many species of brown algae are
extract, and Polypodium leucotomos extract [30]. A study protective against photo-oxidative stress [75]. With con-
of 68 participants observed that soy moisturizer containing troversies around chemical sunscreens and their effects on
soybean-derived serine protease inhibitors (soybean trypsin marine life, algae-derived sunscreens may provide a future
inhibitor and Bowman–Birk protease inhibitor) significantly solution for eco-friendly photoprotection; however, most
improved mottled pigmentation, blotchiness, dullness, fine formulations of sunscreens with MAAs currently contain
lines, overall texture, overall skin tone, and overall appear- only a very small percentage of this active ingredient, and
ance when compared with vehicle [74]. This positive clinical it functions as an adjuvant to UV filters and other sources
effect may be related to the role of soybean-derived ser- of photoprotection [83].
ine protease inhibitors on the regulation of keratinocytes Polypodium leucotomos extract (PLE) is derived from
through keratinocyte protease-activated receptor 2, but a tropical fern found in Central and South America and
additional studies must be performed to further elucidate has antioxidative, chemoprotective, immunomodulatory,
its mechanism [74]. and anti-inflammatory effects [84, 85]. In a recent study
Polyphenols are found in many botanicals, includ- of 22 individuals irradiated with UVB, UVA, and VL, oral
ing tea leaves, grape seeds (Vitis vinifera), blueberries, PLE demonstrated suppressive effects on UVB-induced
almond seeds, and pomegranate extract [75]. In a study of erythema within 2 h of administration [84]. Oral PLE
five participants, sunscreen compounded with tea extracts demonstrated similar photoprotective effects against VL.
containing polyphenols such as epigallocatechin-3-gallate In a cross-over study, subjects taking PLE 480 mg daily

826 L. L. Guan et al.

demonstrated a significant decrease in persistent pigment Conflict of interest  LG has no conflicts of interest that are directly rele-
darkening, delayed tanning, and cyclooxygenase-2 com- vant to the content of this article. HWL has served as coinvestigator for
studies sponsored by Incyte, L'Oreal, Pfizer, and PCOI; as consultant
pared with pre-PLE [86, 87]. Oral PLE should be taken for Pierre Fabre, ISDIN, Ferndale, La Roche-Posay, and Beiersdorf;
daily to receive benefit and is meant to be an adjuvant to and as a speaker on general educational sessions for La Roche-Posay
sunscreen, not a replacement. Topical formulations of PLE and Cantabria Labs. TFM has served as subinvestigator for Allergan
were also effective in reducing sunburn cells and reducing and Ferndale Laboratories.
CPD in an in vitro reconstructed human epidermis model Availability of data and material  Not applicable.
[87]. However, future in vivo studies must be performed to
better assess the feasibility of topical PLE as a sunscreen Ethics approval  Not applicable.
additive.
Consent  Not applicable.
In addition to antioxidants, photolyases are also ben-
eficial additives in sunscreens. Photolyases are enzymes Author contributions  All authors were significant contributors to the
with a unique ability to repair DNA damage, specifically concept and planning, drafting, and revision of the manuscript. All
CPDs. They are flavoproteins and require flavonoids as authors approved the final submitted version of the manuscript.
cofactors to absorb UV radiation. The absorbed energy
from UV radiation is then transferred to damaged DNA
to break CPD bonds in both in vivo and in vitro studies
[30]. It also significantly reduced markers of photoaging References
when added to SPF 50 sunscreen and antioxidants com-
pared with sunscreen alone or sunscreen and antioxidants 1. Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and
[88]. This suggests that photolyases may synergistically therapy. Br J Dermatol. 2007;157:874–87.
2. Sachs DL, Varani J, Chubb H, Fligiel SEG, Cui Y, Calderone K,
enhance the photoprotective effects of sunscreens and anti- et al. Atrophic and hypertrophic photoaging: clinical, histologic,
oxidants [30]. and molecular features of 2 distinct phenotypes of photoaged skin.
J Am Acad Dermatol. 2019;81:480–8.
3. Anti-Aging Products-Market Study by Global Industry Analysts,
Inc. [Internet]. [cited 2021 Mar 10]. Available from: https://​
6 Summary www.​strat​e gyr.​c om/​m arket-​r eport-​a nti-​a ging-​p rodu​c ts-​forec​
asts-​global-​indus​try-​analy​sts-​inc.​asp.
The perception of sunscreen use has shifted from purely 4. Poon F, Kang S, Chien AL. Mechanisms and treatments
protecting against UV-induced erythema to broad-spectrum of photoaging. Photodermatol Photoimmunol Photomed.
2015;31:65–74.
protection against not only erythema but also photoaging, 5. Flament F, Bazin R, Laquieze S, Rubert V, Simonpietri E, Piot B.
dyspigmentation, DNA damage, and photocarcinogenesis. Effect of the sun on visible clinical signs of aging in Caucasian
The impact of visible light and IR light in photoaging is skin. Clin Cosmet Investig Dermatol. 2013;6:221–32.
still being explored, but better methods of protection against 6. Young AR, Claveau J, Rossi AB. Ultraviolet radiation and the
skin: photobiology and sunscreen photoprotection. J Am Acad
these wavelengths are needed. Sunscreens continue to be Dermatol. 2017;76:S100–9.
adapted to provide the broadest coverage while being cos- 7. Miyamura Y, Coelho SG, Schlenz K, Batzer J, Smuda C, Choi
metically appealing. However, with the increased scrutiny W, et al. The deceptive nature of UVA-tanning versus the modest
of UV filters in the 2019 FDA proposed rule, new UV filters protective effects of UVB-tanning on human skin. Pigment Cell
Melanoma Res. 2011;24:136–47.
that are safe for humans and the environment, photostable, 8. Marrot L, Meunier J-R. Skin DNA photodamage and its biological
and consumer friendly must be developed and approved to consequences. J Am Acad Dermatol (Elsevier). 2008;58:S139–48.
offer continued sun protection for US consumers. When 9. de Gruijl FR, Sterenborg HJ, Forbes PD, Davies RE, Cole C,
choosing a sunscreen, a broad-spectrum tinted sunscreen Kelfkens G, et al. Wavelength dependence of skin cancer induc-
tion by ultraviolet irradiation of albino hairless mice. Cancer Res.
with SPF ≥ 30 used daily will offer protection against UVR 1993;53:53–60.
and VL to reduce their effects on photoaging. Additionally, 10. Seité S, Fourtanier A, Moyal D, Young AR. Photodamage to
sunscreen additives such as antioxidants, photolyases, and human skin by suberythemal exposure to solar ultraviolet radia-
more have opened the door for not only improved photopro- tion can be attenuated by sunscreens: a review. Br J Dermatol.
2010;163:903–14.
tection against but also the reversal of skin aging. However, 11. Pillai S, Oresajo C, Hayward J. Ultraviolet radiation and skin
larger-scale and replicable studies must be performed before aging: roles of reactive oxygen species, inflammation and protease
clinical guidelines can be issued. activation, and strategies for prevention of inflammation-induced
matrix degradation—a review. Int J Cosmet Sci. 2005;27:17–34.
12. Battie C, Jitsukawa S, Bernerd F, Bino SD, Marionnet C, Ver-
Declarations  schoore M. New insights in photoaging, UVA induced damage
and skin types. Exp Dermatol. 2014;23:7–12.
Funding  No sources of funding were used to conduct this study or 13. Wang F, Smith NR, Tran BAP, Kang S, Voorhees JJ, Fisher
prepare this manuscript. GJ. Dermal damage promoted by repeated low-level UV-A1
Sunscreens and Photoaging 827

exposure despite tanning response in human skin. JAMA Derma- 33. Wang SQ, Lim HW. Highlights and implications of the 2019 pro-
tol. 2014;150:401. posed rule on sunscreens by the US Food and Drug Administra-
14. Cole C, VanFossen R. Measurement of sunscreen UVA pro- tion. J Am Acad Dermatol. 2019;81:650–1.
tection: an unsensitized human model. J Am Acad Dermatol. 34. Lyons AB, Trullas C, Kohli I, Hamzavi IH, Lim HW. Photoprotec-
1992;26:178–84. tion beyond ultraviolet radiation: a review of tinted sunscreens. J
15. Lee YK, Cha HJ, Hong M, Yoon Y, Lee H, An S. Role of Am Acad Dermatol. 2021;84:1393–7.
NF-κB-p53 crosstalk in ultraviolet A-induced cell death and 35. Geisler AN, Austin E, Nguyen J, Hamzavi I, Jagdeo J, Lim HW.
G1 arrest in human dermal fibroblasts. Arch Dermatol Res. Visible light Part II. Photoprotection against visible and ultraviolet
2012;304:73–9. light. J Am Acad Dermatol. 2021;84:1233–44.
16. Séite S, Moyal D, Richard S, de Rigal J, Lévêque JL, Hourseau C, 36. Lim HW, Kohli I, Granger C, Trullàs C, Piquero-Casals J, Narda
et al. Mexoryl SX: a broad absorption UVA filter protects human M, et al. Photoprotection of the skin from visible light‒induced
skin from the effects of repeated suberythemal doses of UVA. J Pigmentation: current testing methods and proposed harmoniza-
Photochem Photobiol B. 1998;44:69–76. tion. J Invest Dermatol. 2021;S0022-202X(21)01123–4.
17. Mac-Mary S, Sainthillier J-M, Jeudy A, Sladen C, Williams C, 37. Hughes MCB, Williams GM, Baker P, Green AC. Sunscreen and
Bell M, et al. Assessment of cumulative exposure to UVA through prevention of skin aging: a randomized trial. Ann Intern Med.
the study of asymmetrical facial skin aging. Clin Interv Aging. 2013;158:781–90.
2010;5:277–84. 38. Boyd AS, Naylor M, Cameron GS, Pearse AD, Gaskell SA, Neld-
18. McMillan TJ, Leatherman E, Ridley A, Shorrocks J, Tobi SE, ner KH. The effects of chronic sunscreen use on the histologic
Whiteside JR. Cellular effects of long wavelength UV light (UVA) changes of dermatoheliosis. J Am Acad Dermatol. 1995;33:941–6.
in mammalian cells. J Pharm Pharmacol. 2008;60:969–76. 39. Seité S, Fourtanier AMA. The benefit of daily photoprotection. J
19. Cavinato M, Jansen-Dürr P. Molecular mechanisms of UVB- Am Acad Dermatol. 2008;58:S160-166.
induced senescence of dermal fibroblasts and its relevance for 40. Randhawa M, Wang S, Leyden JJ, Cula GO, Pagnoni A, Southall
photoaging of the human skin. Exp Gerontol. 2017;94:78–82. MD. Daily use of a facial broad spectrum sunscreen over one-year
20. Liebel F, Kaur S, Ruvolo E, Kollias N, Southall MD. Irradiation significantly improves clinical evaluation of photoaging. Dermatol
of skin with visible light induces reactive oxygen species and Surg Off Publ Am Soc Dermatol Surg Al. 2016;42:1354–61.
matrix-degrading enzymes. J Invest Dermatol. 2012;132:1901–7. 41. Sabzevari N, Qiblawi S, Norton SA, Fivenson D. Sunscreens: UV
21. Kohli I, Chaowattanapanit S, Mohammad TF, Nicholson CL, filters to protect us: Part 1: changing regulations and choices for
Fatima S, Jacobsen G, et al. Synergistic effects of long-wavelength optimal sun protection. Int J Womens Dermatol. 2021;7:28–44.
ultraviolet al and visible light on pigmentation and erythema. Br 42. Sunscreen Drug Products for Over-the-Counter Human Use
J Dermatol. 2018;178:1173–80. [Internet]. Fed. Regist. 2019 [cited 2021 Mar 22]. Available from:
22. Kohli I, Nahhas AF, Braunberger TL, Chaowattanapanit S, https://​www.​feder​alreg​ister.​gov/​docum​ents/​2019/​02/​26/​2019-​
Mohammad TF, Nicholson CL, et al. Spectral characteristics of 03019/​sunsc​reen-​drug-​produ​cts-​for-​over-​the-​count​er-​human-​use.
visible light-induced pigmentation and visible light protection fac- 43. Forestier S. Rationale for sunscreen development. J Am Acad
tor. Photodermatol Photoimmunol Photomed. 2019;35:393–9. Dermatol (Elsevier). 2008;58:S133–8.
23. Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of vis- 44. Mancuso JB, Maruthi R, Wang SQ, Lim HW. Sunscreens: an
ible light on the skin. Photochem Photobiol. 2008;84:450–62. update. Am J Clin Dermatol. 2017;18:643–50.
24. Lawrence KP, Douki T, Sarkany RPE, Acker S, Herzog B, Young 45. Gabros S, Nessel TA, Zito PM. Sunscreens and photoprotec-
AR. The UV/Visible Radiation Boundary Region (385–405 nm) tion. StatPearls [Internet]. Treasure Island: StatPearls Publish-
damages skin cells and induces “dark” cyclobutane pyrimidine ing; 2021 [cited 2021 Mar 27]. Available from: http://​www.​ncbi.​
dimers in human skin in vivo. Sci Rep. 2018;8:12722. nlm.​nih.​gov/​books/​NBK53​7164/.
25. Cho S, Lee MJ, Kim MS, Lee S, Kim YK, Lee DH, et al. Infrared 46. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Derma-
plus visible light and heat from natural sunlight participate in the tol. 2005;52:937–58.
expression of MMPs and type I procollagen as well as infiltra- 47. Kim EJ, Kim MJ, Im NR, Park SN. Photolysis of the organic
tion of inflammatory cell in human skin in vivo. J Dermatol Sci. UV filter, avobenzone, combined with octyl methoxycinna-
2008;50:123–33. mate by nano-TiO2 composites. J Photochem Photobiol B.
26. Ruvolo E, Fair M, Hutson A, Liebel F. Photoprotection 2015;149:196–203.
against visible light-induced pigmentation. Int J Cosmet Sci. 48. Nedorost S. Ensulizole (phenylbenzimidazole-5-sulfonic
2018;40:589–95. acid) as a cause of facial dermatitis: two cases. Dermatitis.
27. Ma Y, Yoo J. History of sunscreen: an updated view. J Cosmet 2005;16:148.
Dermatol. 2021;20:1044–9. 49. Seité S, Colige A, Piquemal-Vivenot P, Montastier C, Fourt-
28. Aldahan AS, Shah VV, Mlacker S, Nouri K. The history of sun- anier A, Lapière C, et al. A full-UV spectrum absorbing daily
screen. JAMA Dermatol. 2015;151:1316. use cream protects human skin against biological changes occur-
29. Kligman AM. Early destructive effect of sunlight on human skin. ring in photoaging. Photodermatol Photoimmunol Photomed.
JAMA. 1969;210:2377–80. 2000;16:147–55.
30. Yeager DG, Lim HW. What’s new in photoprotection: a review of 50. Mohammad TF, Lim HW. The important role of dermatologists in
new concepts and controversies. Dermatol Clin. 2019;37:149–57. public education on sunscreens. JAMA Dermatol. 2021;157:509.
31. Wang SQ, Xu H, Stanfield JW, Osterwalder U, Herzog B. Com- 51. Matta MK, Florian J, Zusterzeel R, Pilli NR, Patel V, Volpe DA,
parison of ultraviolet A light protection standards in the United et al. Effect of sunscreen application on plasma concentration of
States and European Union through in vitro measurements of sunscreen active ingredients: a randomized clinical trial. JAMA.
commercially available sunscreens. J Am Acad Dermatol (Else- 2020;323:256.
vier). 2017;77:42–7. 52. Matta MK, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Florian J,
32. 14:00-17:00. ISO 24443:2012 [Internet]. ISO. [cited 2021 Mar et al. Effect of sunscreen application under maximal use condi-
21]. Available from: https://w ​ ww.i​ so.o​ rg/c​ ms/r​ ender/l​ ive/e​ n/s​ ites/​ tions on plasma concentration of sunscreen active ingredients: a
isoorg/​conte​nts/​data/​stand​ard/​04/​65/​46522.​html. randomized clinical trial. JAMA. 2019;321:2082.

828 L. L. Guan et al.

53. Suh S, Pham C, Smith J, Mesinkovska NA. The banned sunscreen 72. Oliveira MB, do Prado AH, Bernegossi J, Sato CS, Lourenço
ingredients and their impact on human health: a systematic review. Brunetti I, Scarpa MV, et al. Topical application of retinyl palmi-
Int J Dermatol. 2020;59:1033–42. tate-loaded nanotechnology-based drug delivery systems for the
54. Abbasi J. FDA trials find sunscreen ingredients in blood, but risk treatment of skin aging. BioMed Res Int. 2014;2014:632570.
is uncertain. JAMA. 2020;323:1431–2. 73. Boudreau MD, Beland FA, Felton RP, Fu PP, Howard PC, Mel-
55. Fivenson D, Sabzevari N, Qiblawi S, Blitz J, Norton BB, Nor- lick PW, et  al. Photo-co-carcinogenesis of topically applied
ton SA. Sunscreens: UV filters to protect us: Part 2—increasing retinyl palmitate in SKH-1 hairless mice. Photochem Photobiol.
awareness of UV filters and their potential toxicities to us and our 2017;93:1096–114.
environment. Int J Womens Dermatol. 2021;7:45–69. 74. Wallo W, Nebus J, Leyden JJ. Efficacy of a soy moisturizer in
56. Valisure Detects Benzene in Sunscreen [Internet]. Valisure. 2021 photoaging: a double-blind, vehicle-controlled, 12-week study. J
[cited 2021 Jul 6]. Available from: https://w ​ ww.v​ alisu​ re.c​ om/b​ log/​ Drugs Dermatol JDD. 2007;6:917–22.
valis​ure-​news/​valis​ure-​detec​ts-​benze​ne-​in-​sunsc​reen/. 75. Dunaway S, Odin R, Zhou L, Ji L, Zhang Y, Kadekaro AL. Natu-
57. Valisure. Re: Valisure Citizen Petition on Benzene in Sunscreen ral antioxidants: multiple mechanisms to protect skin from solar
and After-sun Care Products [Internet]. [cited 2021 Jul 26]. Avail- radiation. Front Pharmacol. 2018;9:392.
able from: https://​www.​valis​ure.​com/​wp-​conte​nt/​uploa​ds/​Valis​ 76. Bhattacharya S, Sherje AP. Development of resveratrol and green
ure-​Citiz​en-​Petit​ion-​on-​Benze​ne-​in-​Sunsc​reen-​and-​After-​sun-​ tea sunscreen formulation for combined photoprotective and anti-
Care-​Produ​cts-​v9.7.​pdf. oxidant properties. J Drug Deliv Sci Technol. 2020;60:102000.
58. US Department of Commerce NO and AA. Sunscreen chemicals 77. Rezzani R, Rodella LF, Favero G, Damiani G, Paganelli C, Reiter
and marine life [Internet]. [cited 2021 Mar 27]. Available from: RJ. Attenuation of ultraviolet A-induced alterations in NIH3T3
https://​ocean​servi​ce.​noaa.​gov/​news/​sunsc​reen-​corals.​html. dermal fibroblasts by melatonin. Br J Dermatol. 2014;170:382–91.
59. Tsatalis J, Burroway B, Bray F. Evaluation of “reef safe” sun- 78. Janjetovic Z, Jarrett SG, Lee EF, Duprey C, Reiter RJ, Slominski
screens: labeling and cost implications for consumers. J Am Acad AT. Melatonin and its metabolites protect human melanocytes
Dermatol (Elsevier). 2020;82:1015–7. against UVB-induced damage: Involvement of NRF2-mediated
60. Mitchelmore CL, Burns EE, Conway A, Heyes A, Davies IA. A pathways. Sci Rep. 2017;7:1274.
critical review of organic ultraviolet filter exposure, hazard, and 79. Janjetovic Z, Nahmias ZP, Hanna S, Jarrett SG, Kim T-K, Reiter
risk to corals. Environ Toxicol Chem. 2021;40:967–88. RJ, et al. Melatonin and its metabolites ameliorate ultraviolet
61. Chen L, Hu JY, Wang SQ. The role of antioxidants in photoprotec- B-induced damage in human epidermal keratinocytes. J Pineal
tion: a critical review. J Am Acad Dermatol. 2012;67:1013–24. Res. 2014;57:90–102.
62. Wang SQ, Osterwalder U, Jung K. Ex vivo evaluation of radical 80. Yang G, Cozad MA, Holland DA, Zhang Y, Luesch H, Ding Y.
sun protection factor in popular sunscreens with antioxidants. J Photosynthetic production of sunscreen shinorine using an engi-
Am Acad Dermatol. 2011;65:525–30. neered cyanobacterium. ACS Synth Biol. 2018;7:664–71.
63. Matsui MS, Hsia A, Miller JD, Hanneman K, Scull H, Cooper KD, 81. Pandika M. Looking to nature for new sunscreens. ACS Cent Sci.
et al. Non-sunscreen photoprotection: antioxidants add value to a 2018;4:788–90.
sunscreen. J Investig Dermatol Symp Proc. 2009;14:56–9. 82. Ryu B, Qian Z-J, Kim M-M, Nam KW, Kim S-K. Anti-photoag-
64. Lin F-H, Lin J-Y, Gupta RD, Tournas JA, Burch JA, Selim MA, ing activity and inhibition of matrix metalloproteinase (MMP)
et al. Ferulic acid stabilizes a solution of vitamins C and E and by marine red alga, Corallina pilulifera methanol extract. Radiat
doubles its photoprotection of skin. J Invest Dermatol (Elsevier). Phys Chem. 2009;78:98–105.
2005;125:826–32. 83. Lawrence KP, Long PF, Young AR. Mycosporine-like amino acids
65. Murray JC, Burch JA, Streilein RD, Iannacchione MA, Hall RP, for skin photoprotection. Curr Med Chem. 2018;25:5512–27.
Pinnell SR. A topical antioxidant solution containing vitamins 84. Kohli I, Shafi R, Isedeh P, Griffith JL, Al-Jamal MS, Silpa-archa
C and E stabilized by ferulic acid provides protection for human N, et al. The impact of oral Polypodium leucotomos extract on
skin against damage caused by ultraviolet irradiation. J Am Acad ultraviolet B response: a human clinical study. J Am Acad Der-
Dermatol. 2008;59:418–25. matol. 2017;77:33-41.e1.
66. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical treti- 85. Delgado-Wicke P, Rodríguez-Luna A, Ikeyama Y, Honma Y,
noin for photoaged skin. J Am Acad Dermatol (Elsevier). Kume T, Gutierrez M, et al. F ­ ernblock® upregulates NRF2 anti-
1986;15:836–59. oxidant pathway and protects keratinocytes from PM2.5-Induced
67. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl xenotoxic stress. Oxid Med Cell Longev. 2020;2020:2908108.
G. Retinoids in the treatment of skin aging: an overview of clinical 86. Mohammad TF, Kohli I, Nicholson CL, Treyger G, Chaowattana-
efficacy and safety. Clin Interv Aging. 2006;1:327–48. panit S, Nahhas AF, et al. Oral polypodium leucotomos extract
68. Rosenthal A, Stoddard M, Chipps L, Herrmann J. Skin cancer and its impact on visible light-induced pigmentation in human
prevention: a review of current topical options complementary to subjects. J Drugs Dermatol JDD. 2019;18:1198–203.
sunscreens. J Eur Acad Dermatol Venereol. 2019;33:1261–7. 87. Torricelli P, Fini M, Fanti PA, Dika E, Milani M. Protective effects
69. Kryczyk-Poprawa A, Kwiecień A, Opoka W. Photostability of Polypodium leucotomos extract against UVB-induced damage
of topical agents applied to the skin: a review. Pharmaceutics. in a model of reconstructed human epidermis. Photodermatol Pho-
2019;12:10. toimmunol Photomed. 2017;33:156–63.
70. Benevenuto CG, Matteo MASD, Campos PMBGM, Gaspar LR. 88. Emanuele E, Spencer JM, Braun M. An experimental double-blind
Influence of the photostabilizer in the photoprotective effects of irradiation study of a novel topical product (TPF 50) compared
a formulation containing UV-filters and vitamin A. Photochem to other topical products with DNA repair enzymes, antioxidants,
Photobiol. 2010;86:1390–6. and growth factors with sunscreens: implications for preventing
71. Farooq U, Mahmood T, Shahzad Y, Yousaf AM, Akhtar N. skin aging and cancer. J Drugs Dermatol. 2014;13:309–14.
Comparative efficacy of two anti-aging products containing reti-
nyl palmitate in healthy human volunteers. J Cosmet Dermatol.
2018;17:454–60.