Chronic Actinic Damage of Facial Skin ¨ urkcan MD Cemal Bilac¸ MD, Mustafa Turhan S¸ahin MD, Serap Ozt¨ PII: DOI: Reference:
S0738-081X(14)00048-0 doi: 10.1016/j.clindermatol.2014.02.014 CID 6831
To appear in:
Clinics in Dermatology
¨ urkcan Serap, Please cite this article as: Bila¸c Cemal, S¸ahin Mustafa Turhan, Ozt¨ Chronic Actinic Damage of Facial Skin, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.014
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Chronic Actinic Damage of Facial Skin
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Cemal Bilaç*,MD, Mustafa Turhan Şahin, MD, Serap Öztürkcan, MD From:
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Celal Bayar University, Department of Dermatology, 45020, Manisa, Turkey
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*Corresponding author. Tel: +905055527275, e-mail adress:
[email protected] ACCEPTED MANUSCRIPT
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Chronic actinic damage of the skin manifests itself as extrinsic skin aging (photoaging) and photocarcinogenesis. During the last decade, substantial progress has been made in understanding
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cellular and molecular mechanisms of photoaging. DNA photodamage and ultraviolet-generated reactive oxygen species are the initial events that lead to most of the typical histological and clinical
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manifestations of chronic photodamage of the skin. Chronic actinic damage affects all layers of the skin. Keratinocytes, melanocytes, fibroblasts, and endothelial cells are altered by ultraviolet radiation, and can result in numerous changes in human skin, particularly the skin of fair-skinned individuals. These changes include actinic keratosis, thickening and wrinkling, elastosis,
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telengiectasia, solar comedones, diffuse or mottled hyperpigmentation and skin cancers. There are many options in the treatment of changes caused by chronic actinic damage. However, the most
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effective measure of prevention of the photoaging and photocarcinogenesis is sun protection.
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Introduction
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A century ago, it was considered vulgar by the middle and upper socioeconomic classes to have suntanned skin. Bodies were covered, and hats were worn to prevent sun damage. The only people
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who showed the effects of habitual exposure to the sun were outdoor manual workers. After World War II, all this changed. Starting in the late 1940s, society decided that tanned skin looked healthy.
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The healthy tanned look was considered socially desirable. As a result, skin changes from habitual exposure to sunlight are now more common and more extensive and appear at an earlier age than they did in the 1940s.1 In the past 50 years there have been dramatic changes in life-style, such as vacations in sunny climates in the winter, population shifts toward sunnier climates, more outdoor
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living, and greater emphasis on tanning especially with artificial light sources (tanning studios). All these factors have contributed to overhelm the skin’s intrinsic defense and regeneration
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mechanisms, leading to an increase in photoaging and carcinogenesis. The loss of atmospheric ozone
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has also contributed by allowing more UVB light to reach the Earth’s surface, but this contribution is far less than that of lifestyle changes.2
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Exposure to the sunlight, especially ultraviolet radiation (UVR), is a major environmental risk factor for inflammation of the skin, immune alterations and premature skin aging and, above all, the main risk factor for cancerous degeneration. Cutaneous photoageing is a complex biological process affecting all layers of the skin.3 Photoaging is a cumulative process which depends on the degree of ultraviolet (UV) exposure and the skin type. It is much more visible in individuals with skin types I and II, blue or green eyes, blond or red hair, and less prominent in dark-skinned population.1,4-7 Individuals with outdoor life-styles and people who live in sunny geographical areas will experience the greatest degree of photoaging. Chronic sun exposure can result in numerous changes in human skin, particularly on the face, nape, and arms. Keratinocytes, melanocytes, fibroblasts, and endothelial cells are altered by UV radiation.
ACCEPTED MANUSCRIPT Therefore, changes
in photoaging
include
wrinkling, elastosis, actinic keratosis, irregular
pigmentation, telangiectasia, and the development of malignant skin tumors.4
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Morphologic changes in extrinsically aged skin are accumulation of abnormal elastic tissue in the
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dermis, sparse distribution of collagen fibers, increased collagen degradation, stellate phenotype of fibroblasts and increased biosynthetic activity, increased levels of dysfunctional glycosaminoglycans
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and proteoglycans, increased numbers of mast cells and neutrophils, flattening of the dermoepidermal junction, reduction of anchoring fibrils, thickening of the vascular walls of
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postcapillary venules and of arterial and venous capillaries, increased number of veil cells, and marked regression and disorganization of small blood vessels, impaired proliferation, differentiation,
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desquamation and apoptosis of keratinocytes and thickening of epidermis.8
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Molecular Mechanisms of Actinic Damage
Approximately 5% of the UVR incident on skin is diffusely reflected, the remainder being transmitted,
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scattered and absorbed, or passed out of medium.9
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In the last decades, important progress has been made in understanding molecular mechanisms of photoaging. It is a complex process in which UV radiation has effects on numerous molecular processes that damage the skin, especially connective tissue of the skin. These processes include cell surface receptors, certain signal transduction pathways, transcription factors and, various enzymes involved in the synthesis and degradation of the dermal elements. Initial process in the activation of this process is UV-induced generation of the reactive oxygen species, which can also directly damage cell's DNA, membrane and proteins. Most of alterations found on the photoaged skin had formerly been considered to be caused by ultraviolet B (UVB) wavelengths. However, a number of recent studies have demonstrated that ultraviolet A (UVA) can also cause burning, elastosis, and skin cancer.4
ACCEPTED MANUSCRIPT The electromagnetic spectrum emitted by the sun ranges from the very short cosmic rays to the very long radio waves and beyond. About 9% of solar radiation is in the form of UVR. Most of the
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photocutaneous changes that occur are due to UVR. Of the UVB radiation reaching the skin, 70% is
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absorbed by the stratum corneum, 20% reaches the viable epidermis, and only 10% reaches the upper part of the dermis. UVA radiation is absorbed partly by the epidermis, but 20% to 30% of this
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radiation reaches the deep dermis. Thus, UVA rays are more penetrating than UVB rays. The major chromophores that determine the depth of penetration are nucleic acids, aromatic amino acids, and
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melanin.10
UVB (280-320 nm) and UVA (320-400 nm) are essential components of sunlight that generate severe oxidative stress in skin cells via interaction with intracellular chromophores and photosensitizers,
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resulting in transient and permanent genetic damage, and in the activation of cytoplasmic signal transduction pathways related to growth, differentiation, replicative senescence and connective
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tissue degradation.11
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Oxidative Stress: Initial step is UV-induced generation of the reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radical, superoxide anion, peroxide and singlet oxygen, which can also
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directly damage cell’s DNA, cell membranes and proteins. This damage and structural and functional alterations of cutaneous proteins contributes to aging.
4,7,12,13
Oxidative stress seems to be an
important mechanism of skin aging.14,15 ROS also play a substantial role in collagen metabolism. ROS not only directly destroy interstisial collagen, but also inactivate tissue inhibitors of metalloproteases and induce the synthesis and activation of matrix-degrading metalloproteases.11 The degradative pathway of extracellular collagen fibres is regulated by the matrix metalloproteinase (MMP) and its tissue inhibitor of metalloproteinase (TIMP).13 Under basal conditions, MMPs are part of a coordinated network and are precisely regulated by their endogenous inhibitors, i.e. TIMPs. An imbalance between activation of MMPs and their respective TIMPs could lead to excessive proteolysis.16 Singlet oxygen and H2O2
ACCEPTED MANUSCRIPT are the major ROS involved in the UVA-dependent induction of MMP-1, MMP-2 and MMP-3 on mRNA and protein levels.11
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Ultraviolet A radiation has been reported to stimulate collagenase (MMP-1) synthesis by human skin
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fibroblasts, which may contribute to the connective tissue damage induced by UVR leading to photoaging. Ultraviolet A-induced interleukin (IL)-1a and IL-1b play a central role in the induction of
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the synthesis of both IL-6 and collagenase, suggesting that the UV induced cytokine network may contribute to the loss of interstitial collagen in cutaneous photoaging. Another possibility is that ROS
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produced by UVA may contribute to the biological changes in the connective tissue matrix by accelerating the MMP-related matrix degradation system, as ROS induced by an enzymatic system resulted in a dose-dependent increase in the level of MMP mRNA and a decrease in the level of TIMP
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mRNA in the same fibroblasts.13
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Recently, ROS have been reported to enhance tropoelastin mRNA levels.17 Modulation of Signal Transduction:
UV irradiation invokes a complex sequence of specific
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molecular responses that damage skin connective tissue. The cellular machinery that mediates UV damage to human skin connective tissue includes cell surface receptors, protein kinase signal
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transduction pathways, transcription factors, and enzymes that synthesize and degrade structural proteins in the dermis that confer strengh and resiliency to skin.7 ROS activate cell surface receptors including receptors for epidermal growth factor (EGF), IL-1, insulin, keratinocyte growth factor (KGF) and tumor necrosis factor-alpha (TNF-alpha).7,18 Receptor activation leads to intracellular signalling through stimulation of the stress-associated mitogen– activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK), p38 and cJun amino terminal kinase (JNK). Kinase activation induces the transcription of the nuclear transcription complex AP-1, composed of the proteins cJun and CFos.12,18
ACCEPTED MANUSCRIPT Thus, activated cell surface receptors stimulate signal transduction cascades which induce transcription factor AP-1 resulting in transcription of matrix metalloproteinase genes (MMP-1, 3, and
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9). Additionally, AP-1 in fibroblasts inhibits procollagen gene expression by binding and sequestering
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factors which are part of a transcription complex necessary for procollagen synthesis. MMPs (i.e. collagenase, gelatinase, and stromelysin-I) which are secreted from keratinocytes and fibroblasts
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breakdown collagen, elastin, and other extracellular matrix proteins. These processes result in a drastic change in homeostasis of dermal connective tissue with the development of solar
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elastosis.4,7,12
In addition to receptor activation, UV generates ROS, which damage membrane lipids leading to ceramide release followed by AP-1 activation. Increased AP-1 transcription and activity interferes
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with synthesis of the major dermal collagens I and III as it blocks the effect of transforming growth factor-beta (TGF-beta), a cytokine that enhances collagen gene transcription and negatively regulates
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keratinocyte proliferation. UV irradiation activates the nuclear factor-κB (NF- κB) transcription factor that induces the expression of proinflammatory cytokines such as IL-1, IL-6, vascular endothelial
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growth factor (VEGF) and TNF-beta, proteins involved in immunoregulation and cell survival, and
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stimulates the expression of MMPs.18 UV irradiation leads to decreased expression of transforming growth factor-beta (TGF-beta), and decreased expression of TGF-beta causes decreased collagen production.7,19
Melanocytes are influenced by a number of factors, some of which increase their number and production of melanin. These factors include cytokines (IL-1, IL-6, IL-8, TNF-alpha, TGF-beta), and growth factors (BFGF, endothelin derivates, and nerve growth factor). These molecules have a direct effect on melanocyte proliferation and survival and play a role in the pathogenesis of pigmentary changes of photoaged skin. Additionally, inflammatory mediators formed during UV exposure, such as leukotriene C1, stimulate growth of melanocytes and modifications in the normal melanocyte phenotype.12
ACCEPTED MANUSCRIPT Mutations of Mitochondrial DNA:
Photoaged skin is characterized by increased mutations of the
mitochondrial genome.16 Mutations of mitochondrial DNA (mtDNA, such as the 4977 base-pair large-
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scale deletion, also called common deletion), are increased up to 10-fold in photoaged skin.16,20,21
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Repetitive UV exposure led to an approximately 40% increase in the levels of the common deletion in normal human skin. The majority deletions were detectable in fibroblasts, but also in cultured
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keratinocytes by repetitive UV exposure. These mutations seem to represent long-term in-vivo biomarkers for actinic damage in the human skin.20,22,23 The amount of the common deletion in
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human skin does not correlate with chronological aging, and it has therefore been proposed that mtDNA mutations such as the common deletion represent molecular markers for photoaging.21,24 The resulting decrease in mitochondrial function in photodamaged skin leads to further accumulation of ROS and further compromises the cell ability to generate energy.21 The common deletion was
Telomeres are tandem repeats of a short sequence TTAGGG and its
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Telomere shortening:
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found to be associated with an increased expression of the collagen-degrading enzyme MMP-1.25
complement that are identical in all mammalian cells.16,21 The final 100-200 bases of the telomeres
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are lost with each cell division, and when telomeres reach a critically short length the cell will no
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longer divide and enters a state of replicative senescence.21,26 In addition, telomeres participate in DNA damage responses when ‘uncapped’, leading to telomere-generated signalling that may eventuate in apoptosis or senescence. When telomeres are damaged as a result of UV irradiation or other agent, the overhang becomes exposed and through interaction with the Werner protein activates the tumous supressor protein p53 and other DNA damage response proteins to induce proliferative senescence or apoptosis.21
ACCEPTED MANUSCRIPT Photocarcinogenesis The most deleterious effect of UVR is the development of various types of skin malignancies.4 UVR is
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a known carcinogen and excessive exposure insreases the risk of skin cancers, such as basal cell
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carcinoma (BCC), squamous cell carcinoma (SCC), and cutaneous melanoma.27-29
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SCC and BCC occur overhelmingly in habitually sun-exposed skin of fair-skinned individuals. At least two-thirds of all melanomas are also epidemiologically linked to sun exposure, although these lesions
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tend to occur in intensely but intermittently sun-exposed skin, rather than in areas with maximal lifetime exposure.21
Both UVA and UVB are involved in the pathogenesis of skin cancers. Several recent studies indicated a correlation between chronic cumulative sun exposure and SCC. Exposure to sunlight in early life
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and intense intermittent (reactional) sun exposure seem to be the most important factors involved in
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the onset of BCC and MM.3 Human epidemiological and animal studies strongly suggest that chronic cutaneous UVB and, to a lesser extent, UVA exposure are responsible for the induction of most non-
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melanoma skin cancers, and probably of melanomas.9
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The initiating events seem to be DNA damage and trans to cis urocanic acid isomerization. As a result of these alterations, various cytokines, histamine, neuropeptides are produced. These mediators act on different skin and blood cell populations. DNA damage can induce mutations in oncogenes and tumour supressor genes. These mutations may lead to gene dysfunction.10 UVR radiation can damage DNA, causing gene mutations and, leading to the development of malignant tumours such as BCC, SCC and melanoma. UVB primarily affects the epidermis causing disruption in DNA and the formation of pyrimidine dimers which leads to modifications in oncogene and tumour suppressor gene expression.4 UV-induced mutations in key cell cycle regulatory genes are widely believed to be the principal cause of all three types of skin malignancies. Particularly for SCC, a causative role for UV-induced DNA
ACCEPTED MANUSCRIPT damage has been established by the finding of p53 mutations at pyrimidine sites CC→TT or C→T, the so-called ‘UV-signature’ mutations. UV signature p53 mutations are also very common in actinic keratoses and BCC. However the patched gene (PTCH), growth promoting smoothened (SMO), and
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sonic hedgehog (SHH) gene, which regulates cellular proliferation, are spesifically mutated in BCC.9,21 Cellular DNA directly absorbs UVB, and this absorption causes lesions at the pyrimidine bases, which
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become covalently linked and distort the DNA helix. These lesions are cyclobutanepyrimidine dimers (CPDs), 6-4 photoproducts (6-4 PPs), and Dewar isomers (formed by photoisomerization of 6-4 PPs).
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The CPDs are the most abundant and probably the most cytotoxic lesions as they block transcription and replication. If they are not repaired, they can lead to misreading of the genetic code and cause mutations and cell death. UVA radiation also damages the DNA but less than UVB radiation. UVA
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damage is induced indirectly, through absorption by other endogenous chromophores that release reactive forms of oxygen. These free radicals alter the purines or cause strand breaks. The most
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abundant UVA-induced DNA lesion, 8-hydroxy-2’deoxyguanosine (8-OHdG), is highly mutagenic if not
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repaired.10
UVR also diminishes the immune response in the skin. UVR may promote cancer through indirect
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mechanisms, e.g. immunosuppression and dysregulation of growth factors. The carcinogenic process probably involves multiple sequential steps, some, but not all of which involve alterations in DNA structure.4
Photoimmunosuppression plays an important role in the development of skin cancer. Exposure to UVR depresses cell-mediated immunity. This is partly due to reduction in Langerhans cell numbers and function but also due to an effect on the balance of cis-trans isomerization of urocanic acid and on lymphocyte trafficking. The depressed immunity may be part of the mechanism of photocarcinogenesis.10,30 High cumulative exposure to UVR has also been implicated in the development of sebaceous gland carcinoma, as it is often located on the head and neck area.31,32
ACCEPTED MANUSCRIPT Clinical & Histological Manifestations of Chronic Actinic Damaged Skin Clinical signs of photoaging include dryness, sallowness, fine and severe wrinkling with deep furrows,
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irregular, dark/light pigmentation, laxity, elastosis (a coarse, yellow, cobblestoned effect of the skin),
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pebbling, leathery appearence, telengiectases, premalignant (actinic keratoses) and malignant (SCC,
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BCC, malignant melanoma) lesions.1,4,19,33 Epidermal changes:
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Keratinocyte related changes: Numerous changes were noted in the epidermis of photodamaged skin.12 These included cell heterogeneity, vacuolization, dysplasia, and necrosis. The keratinocytes were noted to be disarray, with nuclear atypia, disorderly maturation, atypical shape, size, and/or staining, and loss of polarity.4,5,12,21 The epidermis contained intercellular and intracellular vacuoles in
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the basal and spinous layers. These vacuoles distorted both basal cells and melanocytes. Large, pale, staining cells were present in the spinous layer. Additionally, fewer Langerhans cells were present in
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severely photodamaged skin.12 Increased compaction of stratum corneum, increased thickness of
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granular cell layer, reduced epidermal thickness and reduced epidermal mucin content lead to
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dryness (roughness) in photodamaged skin.21 Actinic keratoses are scaly, erythematous lesions presenting on sun-exposed areas of the body.34 (Figure 1). These lesions, which sharply demarcated, irregular, maplike thickenings of the horny layer, vary from having an atrophic, telengiectatic, slightly scaly surface to having a thick central keratotic horn.1 More pronounced keratinocyte damage, nuclear atypia and disorderly maturation, so-called ‘loss of polarity’ in the epidermis, is perceived clinically as an actinic keratosis.4,35 In habitually sunexposed skin, numerous are common. Sometimes melanocytes overproduce melanin and give solar keratoses dirty brown color.1 The role of the UVR in the development of seborrheic keratoses is unclear, however, there are authors who believe that sunlight plays an important role in their development. The most common
ACCEPTED MANUSCRIPT sites of the flat, tan-pigmented form of seborrheic keratoses are the dorsal sides of the hands and face.4 Pigmented seborrheic keratoses has variable amounts of melanin pigmentation. Melanocytes are present in the basal layers of seborrheic keratoses and in suprabasal locations. Melanosomes are
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transferred to epidermal keratinocytes and are found predominantly in the keratosis.12 Melanocyte related changes: The density of melanocytes (cells per unit area of skin surface)
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decrease progressively during adulthood by approximately 10-20% per decade. However, with longterm sun exposure, the density of melanocytes increases and is approximately two-fold higher than
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in sun-protected skin.12,35 Depending on the individual's complexion and total insolation, within a few decades exposed skin becomes chronically hyperpigmented (`tanned' or `bronzed'), remaining darker than the sun-protected skin indefinitely, even in the absence of further sun exposure, in part because of increased melanocyte density and increased epidermal melanin and in part because of increased
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number of dermal melanophages.37 Changes in melanocyte number and function are also prominent
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in sun-exposed skin, beginning in childhood.38
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Heterogeneity in skin colour in exposed areas of skin is due to uneven distribution of pigment cells, a local loss of melanocytes, and a modification in the interactions between melanocytes and
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keratinocytes.39 Pigmentary alterations associated with photoaged skin are of several varieties, included hypermelanosis as well as hypomelanosis. Mottled hyperpigmentation, diffuse hyperpigmentation (Increased number of dopa-positive melanocytes, increased melanin content per unit area and increased dermal melanophages), ephelides (reduced or increased number of hypertrophic, strongly dopa-positive melanocytes), lentigines (elongation of epidermal rete ridges, increases in number and melanization of melanocytes), and pigmented actinic keratoses and seborrheic keratoses are the primary lesions of hypermelanosis. Also the development of malignant lesions, such as lentigo maligna and lentigo maligna melanoma. Guttate hypomelanosis, presenting as white spots, is the primary manifestation of hypomelanosis associated with aged skin.4,12,18,39
ACCEPTED MANUSCRIPT The solar lentigo appears at a later age, mostly in persons with long-term sun exposure. The backs of the hands and face (especially the forehead) are favored sites.40 Histologically, they consist of an
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increase in both number and activity of the melanocytes, as well as a characteristic increased
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prominence of rete ridges with a deeply convoluted dermal-epidermal junction, suggesting that proliferative keratinocytes also contribute in some way to the development of these pigmented
Dermoepidermal junction changes:
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lesions.21,41
The basement membrane at the dermal-epidermal junction of sun exposed skin becomes damaged and multilayered and partly disrupted compared with that of sun-protected skin. Basement
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memrane plays important roles in maintaining healthy epidermis and dermis, and repeated damage
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destabilizes the skin, accelerating the aging process. MMPs and plasmin cause damage of the basement membrane and that it’s reconstruction is enhanced by inhibiting these proteinases, as well
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as by increasing the synthesis of the basement membrane components.42 Type VII collagen containing anchoring fibrils which contribute to the stabilization of the epidermal-dermal junction
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are severely reduced in photoaged skin.11
Dermal changes: Fibroblast-Connective tissue changes: The resident fibroblasts of the dermal connective tissue also reveal characteristic features in photoaged skin. The fibroblasts adopt a stellate phenotype and at the ultrastructural level reveal a highly activated rough endoplasmic reticulum indicating increased biosynthetic activity.11
ACCEPTED MANUSCRIPT Photoaged skin is characterized by alterations to the dermal connective tissue. The extracellular matrix in the dermis mainly consists of type I and type III collagen, elastin, proteoglycans, and
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fibronectin.16
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Collagen makes up 70-80% of the dry weight of the skin and gives the dermis its mechanical and structural integrity. To develop the necessary tensile strengh, collagen fibres must acquire
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intermolecular cross-links. Collagen changes observed in photoaging may be partly explained by collagen cross-links as well as by the unbalanced regulation of collagen production and breakdown.13
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In addition to destruction of existing collagen through activation of MMPs, failure to replace damaged collagen is thought to contribute to photoaging as well. Accordingly, in chronically photodamaged skin, collagen synthesis is downregulated as compared to sun-protected skin.16,43 In particular, collagen fibrils are important for the strength and resilience of skin, and alterations in
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their number and structure are thought to be responsible for wrinkle formation.16
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The most striking histopathological hallmark of photoaged skin, which is termed solar elastosis. The
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massive and nodular accumulation of fibrous to amorphous materials with the staining characteristics of elastin in the superficial dermis, which is characterized bu fine nodularity and/or
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coarseness of the skin.13,18,19 The elastic fibre alterations produced by actinic damage constitute the major cause of the coarseness of the skin. Because fibroblasts are responsible for elastogenesis, it has long been believed that the fibroblasts stimulated to produce elastin by chronic exposure to UV light, may produce an abnormal material that is applied to the microfibrils and is subsequently incorporated into the microfibril-dense zones after fibre assembly. Morphologically, the tortuously fixed elastic fibres imply a loss of both their original elasticity and the ability to restore their shorter and straighter forms.13,44,45 In contrast to the amount of collagens, significant increase in glycosaminoglycans (GAG) as well as the accumulation of elastotic materials. The major skin GAG in human skin are hyaluronic acid (HA) and dermatan sulfate (DS). GAG are composed of repeated disaccharide units and are linked to the
ACCEPTED MANUSCRIPT core protein by means of an oligosaccharide link.13 The total amount of main disaccharide units in facial skin was significantly increased compared with that of inguinal skin if the samples were
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obtained from the same individuals.13,46 Karagas et al. reported that, severe solar elastosis occured
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far more frequently in biopsies from the head and neck than from other sides, and more so in men than women. The prevalence of severe elastosis increase with age among both men and women,
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although the magnitude of the increase appeared stronger among women.29
In summary, collagen fibrils are disorganized and abnormal elastin-containing material accumulates
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in photoaged skin. Biochemical studies have revealed that in photoaged skin levels of types I and III collagen precursors and crosslinks are reduced, whereas elastin levels are increased.16 Crow’s feet:
Lines radiating from the eyes are known as crow’s feet and supposedly are due to
It is chacterized by nodular elastosis with cysts and comedones, and
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Favre-Racouchot disease:
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screwing the eyes up against the sun (Figure 2).30
typically developes in older men, beginning with the development of comedones and numerous
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small cysts and yellow aspect of the skin, due to solar elastosis. Usual site of skin lesions are lateral
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aspects of cheeks, periorbital regions, temples and nose.4 Cutis rhomboidalis nuchae: This condition is characteristic of long term, chronic sun exposure40, and clinically presents with deep furrows in a rhomboid pattern on the nape, associated with thickened skin and yellow plaques (Figure 3).4 Colloid milium:
There are two forms of colloid milium: adult and juvenile. In adult colloid milium
lesions appear in the sun exposed areas of the face, neck, ears, hands, and forearms in middle-aged and older adults, usually men. Lesions often coalesce into plaques. It may be considered a papular variant of solar elastosis. The colloid material is derived from elastic fibers, and solar elastosis is found adjacent to areas of colloid degeneration histologically.40
ACCEPTED MANUSCRIPT Sebaceous gland related changes: While the number of sebaceous glands remains the same during life, sebum levels tend to decrease after menopause in females, whereas no major changes appear
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until the eighth decade of life in men. Reduced androgen levels in aged individuals lead to a slow
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cellular turnover in the sebaceous glands resulting in hyperplasia of the facial sebaceous glands in advanced age.32 The damaging effect of UVR has also been implicated in the development of
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sebaceous glands is currently considered to be far more critical than it was suspected in the past and has been attributed to UVA, as UVA penetrates deeper into the dermis and can reach the sebaceous
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gland.32,47 Prolonged UVR has been shown to cause marked hyperplasia of the sebaceous glands in hairless mice.48 The major clinical manifestations associated with aging changes of the sebaceous glands are skin xerosis, as well as sebaceous gland hyperplasia and sebaceous carcinoma in areas with sebaceous follicles (face and upper trunk). Sebaceous gland hyperplasia can vary in size. The
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lesions occur as yellowish or skin-colored papules and nodules, sometimes with large dilated follicular openings, where sebum can squeezed out. Additionaly, photoageing has been associated
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with the development of benign and malignant sebaceous tumors.32 Sebaceous gland carcinoma is a
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rare cutaneous tumor with an incidence of approximately 0.2% of all skin malignancies. Clinically, the tumor may appear initially as a yellowish papule or nodule and can hardly be differentiated from
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initial stage benign sebaceous gland hypertrophy or from other epithelial tumors at later stages.32,49 Blood vessels related changes: With time and in chronically damaged skin, the number of blood vessels decreases significantly.32 In mildly photodamaged skin, there is venular wall thickening, while in severely damaged skin the vessel walls are thinned, the supporting perivascular veil cells are reduced in number, and the normal supporting perivascular connective tissue framework is replaced by ineffectual degenerate material allowing the small blood vessels to dilate and become telangiectatic.16,30,50 The number of vascular cross-sections is reduced and there are local dilatations, corresponding to clinical telangiectases. Overall, there is a marked change in the horizontal vascularization pattern with dilated and distorted
ACCEPTED MANUSCRIPT vessels. UVB irradiation induce dermal angiogenesis by increased vascular endothelial growth factor (VEGF) expression.16 Sun damaged skin often has a symmetrical diffuse telengiectasia, particularly
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prominent on the cheeks, sides, and wings of the nose and the neck. The telengiectatic changes
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sometimes appear quite suddenly (over 6 to 12 months). Patients often have a hard time believing they are from habitual exposure to the sun years ago.1
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Nails, eccrine and apocrine glands: They are not affected by the sun.1
Treatment
Nowadays there are many options in the treatment of changes caused by photoaging. The most
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effective measure of prevention of the photoaging and photocarcinogenesis is sun protection.4 Photoprotection: Photoprotection refers to measures that can be taken to protect the skin from UV
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damage and is achieved by sunscreens, sun-protective clothing, and sun avoidance. Patients should
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be discouraged from using suntanning beds, educated to avoid midday sun exposure, to participate in outdoor activities early or late in the day, to avoid sunbathing, and to seek shady, covered areas
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rather than direct sunlight.19 Broad-brimmed hats (at least a 3-inch brim) is useful for the protection of face and scalp skin.9,40 Using sun safe practices from childhood may effectively prevent skin damage and aging.6,51,52 Prevention of skin cancer induced by exposure to sunlight must be done by educating the younger age groups of the population.3 Photoprotection is the main preventive measure and can be achieved to a large extent by the use of UV filters. UV filters can be divided into physical filters and organic/chemical filters. Most sunscreens contain a mixture of both types.8 Essentially they are creams, lotions, gels or sprays that are formulated to absorb or reflect solar UVR.30
ACCEPTED MANUSCRIPT UV filters can be grouped into two broad categories: organic (chemical) and inorganic (physical). Available sunscreens, especially those of high SPFs (>30) usually contain both chemical sunscreens
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(such as p-aminobenzoic acid [PABA], PABA esters, cinnamates, salicylates, anthranilates,
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benzophenones, benzylidene camphors [Mexoryl], dibenzoylmethanes [Parsol 1789], Tinosorb S/M, octocrylene, ethylexyl triazone, and polysilicone-15) and physcal agents (zinc oxide, titanium oxide,
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and iron oxide).18,30,40 Organic sunscreens absorb UV, convert it into heat, and thus prevent photons from interacting with molecules in the skin. Inorganic sunscreens contain particles that reflect
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photons away from the skin. Because they reflect visible as well as UV photons, they are often visible on the skin surface and therefore cosmetically undesirable for many users, although ‘micronized’ products are often minimally detectable.18 Inorganic sunscreens contain 10-100 nm particles such as
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zinc oxide or titanium dioxide and they protect against both UVA and UVB irradiation.18,19 Patients should be advised to choose a sunscreen with an SPF of 15 or higher and to apply liberally
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and frequently to all exposed body sites, especially the face and neck. Sunscreens should be applied every 2 to 3 hours, especially if patients are engaged in outdoor activities.19 Sun screens may be
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water resistant (maintaining their SPF after 40 min of water immersion) or waterproof (maintaining
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their SPF after 80 min of water immersion). For outdoor exposure, a sunscreen of SPF 15 or higher is recommended for regular use. Application of the sunscreen at least 20 min before and 30 min after sun exposure has begun is recommended. Sunscreen should be reapplied after swimming or vigorous activity or toweling.40 Emollients: The regular use of emollients gives temporary help in reducing the appearance of lines and wrinkles and by giving an attractive ‘bloom’ to the skin.30 Retinoids: The retinods’ key function in physiology is control of cellular proliferation and differentiation. Topical retinoids have been proven to prevent and repair clinical features of photoaging; these processes are facilitated by an ability to prevent loss of collagen (inhibition of
ACCEPTED MANUSCRIPT collagenase synthesis) from dermis, and stimulate new collagen formation in the papillary dermis of sun-exposed skin.4,53-55
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Available topical retinoids include prescription tretinoin, adapalene, and tazarotene and over-the-
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counter Retinol® and Retinol-A®. In studies, topical tretinoin increased collagen type I in photoaged skin, and improving effect of roughness, dyspigmentation, and fine wrinkles.12,19,40 The topical
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retinoids (tretinoin, isotretinoin, and tazarotene) have all been shown to reduce the signs of solar elastosis. They appear to stimulate the formation of new dermal collagen as well as regularize
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epidermal and melanocyte structure and function. Clinical improvement starts 3-4 months after use of the topical retinoids.30
Hormones: Topical oestrogen treatment of facial skin in menopausal females results in an induction
The delivery of enzymes that repair DNA damage or oligonucleotides that
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DNA repair enzymes:
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of the sebaceous gland activity with increased sebum secretion and a reduction in skin xerosis.56,57
enhance the endogenous capacity for DNA damage repair may prove to be a valuable means to
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achieve protection against UV irradiation and decrease the incidence of photocarcinogenesis. The enzyme T4-endonuclease V (T4N5) recognizes cyclobutane pyrimidine dimers (CPDs), the main DNA
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photolesions induced by UVB, and initiates repair by enhancing their cleavage. Additionally T4N5 decreses the synthesis and release of immunosuppressive cytokines like TNF-alpha and IL-10.18,58 Another enzyme, photolyase, absorbs visible light and utilizes the energy to break up the CPD cyclobutane ring, a mechanism called ‘photoreactivation. Studies using liposome-encapsulated photolyase demonstrate reduced UV-induced apoptosis, decreased CPD levels, and diminished apoptotic cell death.18,59,60 The enzyme oxoguanine glycosylase 1 (OGG1) catalyses the first step in base excision repair, a process that removes the oxidatively damaged guanine bases, 8-oxo-guanine (8oG) from DNA. Plant-derived liposome-encapsulated OGG1 enhances 8oG removal from human epidermal keratinocytes exposed to oxidative damage. Topical application of thymidine
ACCEPTED MANUSCRIPT oligonucleotides could improve the ability of the skin to repair DNA damage without the need for prior UV irradiation.18
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Cosmeceuticals: Cosmetic products containing peptides, antioxidants, and botanicals are examples
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of cosmeuticals.19 Peptides are amino acid chains that are fragments of large proteins such as collagen. Pal-KTTS is a collagen peptide fragment, it may penetrate into the dermis and stimulate
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collagen production.61
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Antioxidants act by reducing free radicals to less reactive molecules, thus reducing oxidative damage to critical cellular constituents.18 Antioxidants are molecules that work in the skin to reduce ROS which are generated by UV damage and lead to breakdown of collagen.19 The topical and peroral adminisration of network antioxidants, such as vitamin E and C, coenzyme Q10, alpha-lipoic acid and enhance
antiaging
effect.
The
other
antioxidants
such
as
green
tea,
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glutathione,
dehydroepiandrosterone, melatonin, selenium and resveratrol, have also antiaging and anti-
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inflammatory effects.55 Products containing alpha-tocopherol (vitamin E), L-ascorbic acid (vitamin C),
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retinol (vitamin A), and niacinamide (vitamin B3), are considered to be effective in the treatment of photoaging.62 Idebenone is a synthetic analog of Coenzyme Q10 with potent antioxidant activity; it
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reduces skin roughness, increases skin hydration, reduces fine lines, and was associated with an improvement in overall global assessment of photoaged skin.63 Topical vitamin C 5% cream application stimulates the collagen producing acitivity of the dermis, and led to clinical improvement in the appearence of photoaged skin with regard to firmness, smoothness, and dryness.64,65 Other naturally occuring antioxidants include polyphenolic molecules (i.e. flavonoids, prozyanidine), genistein, resveratrol, beta-carotene, lycopene, lutein, zeaxanthin, cryptoxanthin, L-ergothioneine. Still, while promising new antioxidant candidates appear to decrease UV-induced detrimental effects in skin, additional long-term studies are required to establish the ability of topically applied or orally administered antioxidants in preventing photoaging and photocarcinogenesis.18
ACCEPTED MANUSCRIPT Alpha-hydroxy acids (AHA) are lactic acid, malic acid, citric acid, and glycolic acid. Topical treatment of photodamaged skin with AHAs has been reported to improve wrinkling, roughness and
Hydroquinone, kojic acid and azelaic acid can reduce signs of aging.55
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Topical bleaching agents:
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dyspigmentation within months of daily application. 18,66-68
Hydroquinone (3-6%) are the mainstay of treatment for most disorders of hyperpigmentation. The
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efficacy of combination therapy in the treatment of solar lentigines and hyperpigmentation has been
Cosmetic procedures:
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for the combination of tretinoin/hydroquinone and the combination 4-hydroxyanisole/tretinoin.12 Superficial, medium, and deep chemical peels may be employed for the
treatment of pigmentary abnormalities and the other effects fo photodamage, such as wrinkles, and actinic keratosis. The spesific agents used include glycolic acid (30-70%), salysilic acid (20-30%),
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trichloroacetic acid (10-25%), and combination peels, including Jessner’s solution (14% salysilic acid, 14% lactic acid, 14% resorcinol in 95% alcohol) and trichloroacetic acid, glycolic acid and
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trichloroacetic acid, and CO2 and trichloroacietic acid.12,69 Studies confirm that, the efficacy of topical
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agents in combination with superficial and/or medium depth or deep peeling agents for photodamaged skin treatment.55
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Photodynamic therapy (PDT): PDT has been shown to be effective in treating nonmelanoma skin cancer, espesicially actinic keratosis, and has the potential to reduce the histological signs of photoaging.70 Surgical Approaches:
Ablative laser resurfacing is considered to be gold standard to improve
clinical features of the aging face and generally refers to treatment with a carbon dioxide laser. It improves fine and some coarse wrinkles and overall dyspigmentation. Non-ablative laser resurfacing procedures are much less invasive than ablative lasers. Select non-ablative lasers include the longpulsed neodymium YAG, radiofrequency, intense pulse light, Q-switched, pulsed-dye and KTP lasers.19
ACCEPTED MANUSCRIPT Neoplastic lesions and damaged skin were removed by superficial erbium laser ablation and the epidermis reconstructed with autologous epidermal sheets expanded in vitro from healthy cells obtained from unexposed areas of the body. This procedure is very effective in the short term for
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treating and preventing the UV-induced skin cancer and precancerous lesions.3
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Dermabrasion and plastic surgery can also reduce or eliminate certain signs of photodamaged skin.4 Botulinum toxin and soft tissue fillers (i.e.hyaluronic acid, calcium hydroxylapatite, poly-L-lactic acid
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and human-based collagen) are also being used for photoaging treatment.19 The treatment of sebaceous carcinoma is the surgical intervention.32 Surgical excision is the most
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suitable treatment for the UV-related skin cancers.
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Conclusion
Today’s lifestyle has resulted in increased sun exposure throughout the whole lifetime. Therefore,
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with the rise in the share of elderly population, there is an increase in the part of population with significantly photodamaged skin. Increased cosmetic consciousness and longer human lifespan
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resulted in the fact that in recent years greater attention has been given to the accelerated signs of aging skin with the emphasis on the role of the UVR. 4 Almost 90% of skin changes due to environmental influence are caused by chronic sun exposure (photoaging). The process of photoaging in elderly adults goes along with characteristic clinical and histological changes associated with the magnitude of cumulative sun exposure.32 Exposure the sunlight, especially UVR, is a major environmental risk factor for inflammation of the skin, immune alterations and premature skin aging and, above all, the main risk factor for cancerous degeneration. Cutaneous photoaging is a complex biological process affecting all layers of the skin.3
ACCEPTED MANUSCRIPT Chronic sun exposure not only causes a cosmetically undesirable appearance but also gives rise to malignant and premalignant lesions. Although there are a lot of treatment alternatives for chronic
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conscious of the importance of sun protection, beginning in early ages.
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sun damage and premalignant as well as malignant lesions, the best approach is to make people
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ACCEPTED MANUSCRIPT 68. DiNardo JC, Grove GL, Moy LS. Clinical and histological effects of glycolic acid at different concentrations and pH levels. Dermatol Surg 1996; 22: 421-4.
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69. Kitzmiller WJ, Visscher MO, Maclennan S, et al. Comparison of a series of superficial chemical
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histological features of actinic damage and the expression of early oncogenic markers. Br J
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