| |

Received: 3 December 2020    Revised: 2 February 2021    Accepted: 16 February 2021

DOI: 10.1111/jocd.14033

REVIEW ARTICLE

The impact of ultraviolet radiation on skin photoaging —­review

of in vitro studies

Krystyna Joanna Gromkowska-­Kępka MSc  | Anna Puścion-­Jakubik PhD  |

Renata Markiewicz-­Żukowska PhD  | Katarzyna Socha PhD

Department of Bromatology, Medical

University of Białystok, Białystok, Poland Abstract
Background: Photoaging, ultra violet (UV) induced skin aging is a gradual process that
Correspondence
Krystyna Joanna Gromkowska-­Kępka, depends on the time and intensity of solar radiation.
Department of Bromatology, Medical
Aim: The aim of this paper was to review of the literature focused on in vitro studies
University of Białystok, Mickiewicza 2D
Street, 15-­222 Białystok, Poland. explaining the mechanisms of photoaging.
Email: krystyna.gromkowska.kepka@
Methods: Electronic databases, including PubMed and MEDLINE, were searched for
gmail.com
in vitro studies on the importance of UV radiation in the skin photoaging process of
peer-­reviewed scientific journals. Only articles available in English and full version
publications were considered for this review.
Results: Three main modes of UV radiation action on skin cells which lead to photo-
aging, there are changes in cell metabolism, induction of oxidative stress due to the
change in enzyme activity.
Conclusion: The information gathered in this publication will help to better under-
stand the complex and multidirectional mechanism of skin photoaging, which will con-
tribute to the development of research on potential cosmetic products that provide
effective and safe sun protection or repair damage caused by UV radiation.

KEYWORDS
fibroblast, keratinocytes, mechanism of photoaging, review, UV radiation

1  |  I NTRO D U C TI O N Nevertheless, the negative impact has been also observed during
skin exposure to infrared radiation (IR; λ = 760 nm−1 mm).3 IR pen-
Skin aging involves internal and external processes. Changes occur- etrates deeper layers of the skin than the rest of optical radiation.
ring as a result of genetic conditions (internal, chronological aging) Even up to 17% of the incident infrared light can directly penetrate
overlap with aging symptoms stimulated by environmental condi- into the subcutaneous tissue. IR is absorbed by tissue chromophores
tions (extrinsic aging). The most harmful external factor threatening (e.g., water) and converted into heat so that deep tissues can be
the skin is ultraviolet (UV) radiation. UV radiation consists of three heated. The heat is then transferred deeper by conduction, and
components: UVA (λ = 320−400 nm), UVB (λ = 280−320 nm) and UVC pathological changes such as skin and corneal burns can occur.4
(λ = 100−280 nm). UVC radiation, unlike UVA and UVB radiation, is The human skin, an important part of the innate immune sys-
almost completely absorbed by the ozone layer. UVA and UVB rays tem, has various molecular mechanisms that protect this organ
reach the earth in sufficient quantities to damage skin structures.1,2 from UV exposure. The first of these is the layered structure of the

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
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© 2021 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

J Cosmet Dermatol. 2021;20:3427–3431. wileyonlinelibrary.com/journal/jocd    3427 |

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3428      GROMKOWSKA-­KĘPKA et al.

epidermis, which provides the first line of defense against harmful Cyclobutane dimers Py (CPD) are mainly induced by UVB, while
external agents. Additionally, immune cells such as Langerhans cells 8-­hydroxy-­2-­deoxyguanine (8-­OHdG) is one of the most common
and T lymphocytes are located within the skin. Another line of pro- markers for the estimate of DNA damage from UVA.
tection for the skin is the melanocytes. Melanin, a pigment synthe- DNA damage is one of the most serious effect of excessive skin
sized by these cells, impedes the penetration of UV radiation into exposure to UV radiation and plays a major role in inducing pho-
the living layers of the epidermis by absorbing it. Furthermore, to tocarcinogenesis and is also directly involved in photoaging. The
maintain homeostasis, UV-­induced DNA damage can be repaired at destructive mechanism of UVB and UVA action on DNA mole-
the molecular level by nucleotide repair and base excision mecha- cules differs, which is related to the amount of energy absorbed by
nisms or apoptotic mechanisms as well as cell cycle checkpoints are base pairs in the DNA chain.17 The direct action of UVB radiation
activated.5,6 on cellular DNA results in characteristic mutations in the structure
UV radiation increases the risk of long-­term damages such as of the nucleic chain, such as the formation of CPD and pyrimidine
photoaging, photoimmunosuppresion, and photocarcinogenesis.1,2 base transverssions.18 DNA damage due to UVA radiation, like UVB,
UVA radiation has its negative effect on the epidermal keratinocytes includes the formation of CPD, pyrimidine (6-­4) pyrimidone photo-
and dermal fibroblast and induces long-­term changes. Changes aris- products, as well as damage to and transition of DNA bases.19,20
ing as a result of UVB radiation are visible mainly within the epider- Exposure to UVA causes direct damage of skin cells through an
mis but it also penetrates the upper part of dermis.7,8 The harmful inflammatory reaction and indirectly through the induced oxidative
effects of ultraviolet exposure mainly include skin side effects such stress. This initiates peroxidation of polyunsaturated fatty acids
as sunburn, photodermatoses, hyperpigmentation, photoaging of (PUFA) in the skin membrane and the formation of DNA adduct,
the skin and precancerous lesions and cancers. The mechanisms dis- 8-­hydroxy-­2'-­deoxyguanosine (8-­OHdG), which is the most numer-
cussed in this paper are involved in the formation of these clinical ous and highly mutagenic factor, considered as a reliable marker for
changes in the skin. oxidative DNA damage. 21,22
Common point of photoaging is less dermal fibers expression.8 Under exposure to UVB radiation on the skin, an inflammatory
Overexposure to UV radiation increases the formation of reactive response is triggered in keratinocytes, resulting in the activation
oxygen species (ROS), which at higher concentrations can damage of the protein kinase R signal transduction pathway, which blocks
the main proteins that make up the skin, collagen and elastin.9–­12 A this signal transduction pathway. A long non-­coding RNA, nc886,
characteristic feature of the skin affected by photoaging is the pres- suppresses the signal transduction pathway with protein kinase R to
ence of solar elastosis in the dermis. Solar elastose is a dystrophic protect the cell from UV radiation. 23
elastic material that is formed as a result of a cycle of processes lead- Autophagy, which is an intracellular cleansing system, is essential
ing to the degradation of elastic fibers, followed by the formation of for maintaining homeostasis in skin structures. In the case of skin
the extracellular matrix (ECM) and its reconnection into a structure aging, the basic level of autophagy increases during the replicable
other than its original one.13 aging of human facial fibroblasts. 24 Furthermore, UVA induce auto-
The first report about the modulating influence of UV radi- phagy in fibroblasts25 and UVB in human keratinocytes. 26 However,
ation on the progress and formation of some dermatoses is dated the process of autophagy is not capable of completely cancelling
14
on 1910. Since then, there has been a lot of research to find out out the aging reaction of these cell types and only delaying it. 27,28
the relationship between solar radiation and skin lesions, both dis- ROS production induced by UV stimulates autophagy, which regu-
ease and esthetic. This review focuses on gathering information lates the reaction to oxidative stress due to solar radiation. Exposure
about photoaging, especially the impact of UV radiation on skin cells to UVA radiation results in an increase in the quantity of oxidized
metabolism, formation of oxidative stress and modulation of skin phospholipids, oxysterols and cholesterols in epidermal cells, which
enzymes. The information collected in this review about the mech- is a signal to induce autophagy in keratinocytes. Autophagy plays a
anisms that are occurring in skin cells under the influence of UVA multiple role in response to oxidative stress caused by UVA radiation
and UVB radiation may be helpful in the search for new, effective by removing oxidized molecules while minimizing the antioxidative
compounds that show protective activity on the skin and reduce the reaction in various cell types. It has been shown that UVA regulates
effects of photoaging. the transcription of a certain of genes which take part in autophagy,
for example adaptive protein p62, as well as autophagic activators
p53 and Sestrin2 (SESN2) that can induce autophagy through 5’
1.1  |  UV and cellular metabolism adenosine monophosphate-­activated protein kinase (AMPK) sig-
nalling. 29 The results of an experiment conducted by Endo et al.
UV radiation can penetrate into the skin and interact with skin cells, (2020) showed that repeated UVA radiation negatively affects the
both fibroblasts and keratinocytes.15 Senescent cells secrete a num- autophagy process in fibroblasts due to modifications in lysosomal
ber of factors such as cytokines, chemokines, growth factors and functioning.30 The impairment of intracellular degradation in UVA-­
matrix metalloproteinases (MMPs), that is known as senescence-­ treated fibroblasts occurs through molecular mechanisms under-
associated secretory phenotype.16 The formation of premutagenic lying impaired autophagy such as decreased lysosomal acidity and
photoproducts is dependent on the type and dose of UV radiation. reduced expression of cathepsins B, L and D.31 That suggests that
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      3429

anomalies in the process of autophagy are the leading agent in the suggest that increased ROS generation and autophagy and reduced
process of photoaging of the skin. However, the basic dysfunctional proteasome activity contribute to the aging of fibroblasts treated
mechanism of lysosomes in repeated UVA radiation fibroblasts is with UVB. Autophagy is necessary to establish the phenotype of
still not clear.30 aging of UVB-­induced fibroblasts, and suppression of autophagy is
Multiple exposition to UVB radiation causes an fail-­safe process needed to modify the path of cells from aging to apoptosis death.39
in the epidermis, which results in the forming of sunburn cells (SBC), Deactivation of proteasomal system in fibroblast cells under the in-
that is, keratinocytes which undergo apoptosis.32 Damages of kera- fluence of UV radiation is associated with the generation of singlet
tinocytes DNA caused by UVB leads to the release of signals which oxygen, oxidation of proteins and activation of transcription agents
initiate the release of inflammatory response mediators, for exam- known from the regulation of MMP-­1 expression.40
ple, cytokines IL-­1α, IL-­6, and TNF-­α .33 UVB directly induces the
AMPK autophagy activator, a gene associated with UV resistance
(UVRAG) and p53. Stabilized by UVB p53, initiates transcription of 1.3  |  UV-­enzymes and fibers
AMPK, SESN2, tuberous sclerosis complex 2 (TSC2), and UVRAG for
activation of autophagy. 29 One of the main effects of UV radiation on the skin is an increase in
expression of MMPs, which are responsible for the degradation of
ECM proteins such as collagen, fibronectin, elastin, and proteogly-
1.2  |  UV and oxidative stress cans.41 Excessive degradation of these proteins caused by excessive
production of MMP-­1, MMP-­3, and MMP-­9 contributes to the pho-
One of the main effects of UV radiation on skin molecules (e.g., uro- toaging of the skin and thus to the formation of thick wrinkles and
canic acid, nicotinamide-­adenine dinucleotide (NADH) or melanin) is sagging of the skin through photodestruction, phototransformation
sensitization to ROS formation from absorbed energy. ROS (e.g., sin- and photooxidation of collagen and elastin.33,42
glet oxygen, hydrogen peroxide, peroxide) are able to react and dam- MMPs play an important role in the development of solar
age most of the molecules in their pathways, such as lipid membranes radiation-­related cancer, as they regulate various processes asso-
of cells, proteins or DNA. Moreover, ROS stimulate cell surface recep- ciated with the cancer process, including tumor location, growth,
tors, especially those for the epidermal growth factor (EGF), keratino- angiogenesis and metastasis.43 The data presented by Dong et al.
cyte growth factor (KGF), interleukin (IL)-­1, and tumor necrosis factor (2008), as the main initiator of processes leading to the induction
(TNF)-­α. In addition, ROS causes damage to the membrane lipids, which of MMP-­1 production, indicate DNA damage caused by UVB radi-
leads to the release of ceramides and then the activation of AP-­1.34 ation. Their studies revealed a more than fourfold increase of the
UVA radiation causes the release of prostaglandin-­F2α (PGF2α) expression of the MMP-­1 gene in keratinocytes mRNA induced by
and 12-­HETE from arachidonic acid (AA) by causing an inflammatory UVB treatment of cells.33 Changes in protein expression play an im-
response in skin and upregulating cyclooxygenase and lipoxygenase portant role in the process of skin photoaging, including the trans-
enzymes. The formation of these metabolites has been found to be forming growth factor-­β (TGF-­β), Smad2, MMP-­1, MMP-­3, MMP-­9.
associated with immunological reactions, inflammatory disorders, Moreover, UV radiation, the increase in the amount of ROS and the
skin pigmentation and the wounds healing.35–­37 Short-­term expo- expression of MMPs, which are one of the major agents involved in
sure of keratinocytes to sunlight may modify the composition of the process of skin changes associated with photoaging, may also in-
PUFA and its metabolism in skin cells. An in vitro study on epidermal teract with catepsins.44–­46 Citing the results of a Zheng et al. (2011)
cells carried out by Leung et al. (2017) has shown that keratinocytes study, the modified gene expression of cathepsins by repetitive
may have defensive mechanisms at exposure to UVA, for example exposures to UVA radiation is a prospective clarification of the al-
raised docosahexaenoic acid (DHA) levels, which prove to be helpful teration of cathepsin activity and content in photoaging skin. Their
in regeneration after potential lesions. 22 results suggest that the level and activity of cathepsins B, D, K and G
The effects of UVB radiation on the generation and release of may be considered as potential biomarkers in photoaging of human
ROS in human keratinocytes have been studied by Beak et al. (2004). skin.44 Cathepsin K is one of the factors involved in the degradation
The results showed an increase in intrinsic cellular production and of elastin, which leads to the formation of solar elastosis. It plays a
release of nicotinamide-­adenine dinucleotide phosphate (NADPH) dominant role in this process due to its elastolytic activity. Cathepsin
oxidase and cyclooxygenase (COX), that might play an essential D is a factor that induces cellular mitosis, which leads to weakening
role in UVB-­induced ROS production and nuclear factor B (NF-­κB) of the immune response and inhibition of dendritic cell function. It is
activation in keratinocytes in a dose-­dependent mode.38 Cavinato assumed that down-­regulation of cathepsin D, as a growth regulator
et al. (2017) have studied the role of protein quality control sys- of keratinocytes, may contribute to photoaging-­related disorders of
tems and their functional interaction in mediating the cellular aging epidermal cell proliferation, such as disorders of the keratinization
of UVB-­treated fibroblasts in vitro. The results suggest that early process. Also cathepsin B is responsible for matrix degradation and
events in the process of senescence of fibroblast after UVB expo- cell invasion.44,45 Another factor responsible for regulating MMP-­1,
sure include increased production of ROS and an inhibition of pro- MMP-­2, MMP-­3, and MMP-­9 in human UVA-­treated fibroblasts is
teasome, followed by initiation of autophagy. The obtained results opsin 3 (OPN3), as first demonstrated by Lan et al. (2020). Through
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3430      GROMKOWSKA-­KĘPKA et al.

a calcium-­dependent signalling pathway coupled with G-­proteins, Anna Puścion-­Jakubik  https://orcid.org/0000-0002-8526-8107

OPN3 initiates the process of transduction in UVA-­exposed fibro- Renata Markiewicz-­Żukowska  https://orcid.
blast cells. OPN3 influences the phosphorylation of activator 1 pro- org/0000-0003-0716-9573
tein and regulates the action of MMPs by activating protein kinase II. Katarzyna Socha  https://orcid.org/0000-0002-5949-7061
The process of activation of protein kinase II is dependent on many
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