CHAPTER 1: Photoaging in Caucasians

Photoaging occurs as a result of exposure to environmental and artificial radiation and involves the superimposition of these extrinsic changes on a background of intrinsic aging. It has become significantly more prevalent in recent years due to changes in social behaviours, leisure activities, lifestyle, travelling and holiday homes abroad.¹  Most studies outlining the incidence of photoaging have been reported from Australia, the USA and the UK. Photoaging may account for 90% of age-associated skin problems in both men and women.^2,3  In an Australian study, clinical changes of moderate to severe photoaging were observed in 72% of men and 47% of women under 30 years of age.⁴  The severity of photoaging directly correlates with advancing age. Even brief, intermittent sun exposure occurring while conducting activities of daily living appeared to add significantly to an average individual's daily ultraviolet radiation (UVR) exposure.⁵  A Northwest England survey concluded that sun exposure received during normal daily activities may be sufficient to produce skin malignancies in a significant proportion of the population.⁶ 

The degree of photoaging is significantly affected by an individual's ethnicity and Fitzpatrick phototype. Fair-skinned individuals of Northern European descent (Fitzpatrick phototypes I–III) are more prone to photoaging than individuals with skin of colour (Fitzpatrick phototypes IV–VI; including people of African, African-American, Asian, and Latino/Hispanic descent),⁷  with melanin affording protection against sun-induced damage.

Among white Northern Europeans, facial photoaging comprises two distinct phenotypes, termed ‘hypertrophic’ photoaging (HP) and ‘atrophic’ photoaging (AP).⁸  In individuals with HP, deep coarse wrinkles predominate, whereas those with AP have relatively smooth, unwrinkled skin with pronounced telangiectasia.⁹  Both phenotypes have distinct histological characteristics. AP has a significantly thicker epidermis than HP.⁸  Further stratification by gender demonstrates that the AP epidermal thickness is significantly increased in males as compared to females.¹⁰  HP photoaged skin exhibits severe solar elastosis, characterized by extensive deposition of amorphous, abnormally thickened, curled and fragmented elastic material in the dermis. In AP photoaged skin, there are gender differences in elastic fibre deposition, in that solar elastosis is apparent in females but not in males.¹⁰  Loss of papillary dermal fibrillin-rich microfibrils is a distinctive feature of photoaging and occurs in both HP subjects and in AP females but not in AP males.¹⁰  It is important for clinicians to recognize that these two distinct phenotypes exist, because individuals with the AP photoaging phenotype have an increased propensity for developing keratinocyte cancers.

The evidence presented here is intended to demonstrate how AP and HP facial photoaging represent distinct clinical and histological entities. In HP skin, the manifestation of wrinkles, the destruction of fibrillin-rich microfibrils and the deposition of elastotic material within the dermis could act synergistically to protect against development of keratinocyte cancers. In contrast, AP males lack coarse wrinkles and solar elastosis yet retain fibrillin-rich microfibrils – all of which may act to promote keratinocyte carcinogenesis. This is an aspect of skin aging and photocarcinogenesis that warrants further exploration.

The skin undergoes two forms of aging: (i) intrinsic or chronological aging, which occurs in its purest sense in sun-protected sites; and (ii) extrinsic aging, mainly induced by chronic exposure to ultraviolet radiation (UVR). Photoaging is the inevitable superimposition of extrinsic, i.e. photodamage on a background of intrinsic aging.^11,12  Table 1.1 summarizes the comparison between the features of intrinsically aged and extrinsically aged skin.

Intrinsic aging is defined by the clinical, histological and physiological decrements that occur in sun-protected areas of skin of older individuals. It affects: the rate of epidermal turnover;¹³  the thickness and cellularity of the dermis;^14,15  re-epithelization after wound healing; immune responsiveness;¹⁶  vitamin D synthesis;¹⁷  and vascular reactivity.¹⁸  There is a paucity of hair follicles, sweat glands and sebaceous glands.^19,20  The signs of intrinsic aging begin at around 50–60 years of age, earlier in women than men,²¹  which is attributed to menopause and a decrease in oestrogen-protective effects on the skin.^22,23  Clinically, intrinsically aged skin appears dry and pale, smooth, thin, transparent, unblemished, and finely wrinkled due to gravitational and conformational forces. It displays a certain degree of laxity and regular pigmentation as well as an increased chance of developing a variety of epithelial neoplasms.²⁴  Fine wrinkles associated with intrinsic aging can occur anywhere on the body surface due to loss of elasticity. Skin sagging also occurs,^11,25,26  but the skin also maintains its youthful geometric surface patterns.¹²  The heterogeneity of pigmentation is mild in comparison to photoaging.²⁶ 

Intrinsic aging is thought to be regulated by a number of mechanisms common to all cell types, such as telomere shortening,^27,28  cellular senescence^29–31  and oxidative stress.^32–35  In intrinsic aging, histological analysis reveals epidermal atrophy, dermal–epidermal junction (DEJ) flattening and elastogenesis.³⁶  Reduplication of the lamina densa remains modest.³⁷  This is reflected by increased fragility of the skin. Basal keratinocytes show some cellular irregularity. Keratinization remains unchanged. There is a reduction in the number and biosynthetic capacity of fibroblasts, resulting in delayed wound healing.³⁸  Epidermal proliferation also declines with a slower desquamation rate.^39–41  This results in a thicker stratum corneum consisting of larger corneocytes. Intercellular lipid production is reduced in the aged epidermis, resulting in a reduced water-holding capacity of the stratum corneum due to a decrease in size of keratohyaline granules containing profilaggrin.^42–44  Fine dermal elastic fibres show evidence of proteolysis and wear, giving a ‘moth-eaten’ appearance. In short, elastic fibres coarsen with age and then disappear. There are modest changes in collagen bundle size and organization; microvasculature retains a normal architecture.⁴⁵ 

In contrast, extrinsic aging (predominantly photoaging) is directly related to environmental factors and occurs in habitually exposed areas of the body such as face, neck, and arms.⁴⁶  Extrinsic aging was first reported at the end of the nineteenth century, described as farmers' or sailors' skin.⁴⁷  Clinically, the features of photoaging include roughness, sallowness, deep wrinkling, dyspigmentation, senile purpura, telangiectasia, and the development of a variety of benign and malignant cutaneous neoplasms.⁴⁸  Hyperpigmented lesions include freckles and lentigenes set amidst a background of diffuse mottling. Deep wrinkles are usually found on the forehead and in the peri-orbital region.⁴⁹  The term dermatoporosis has been used to describe the clinical manifestations of intrinsic aging, but many features overlap with those of photoaging, including skin fragility and atrophy, senile purpura, stellate pseudoscars, dissecting haematomas of the skin, and delayed wound healing.⁵⁰ 

Sun-induced cutaneous changes vary considerably among individuals, reflecting the inherent differences in vulnerability and repair capacity following a solar insult. Fair-skinned individuals of Northern European descent (Fitzpatrick phototypes I–III) are more prone to photoaging than individuals with skin of colour (Fitzpatrick phototypes IV–VI; including people of African, African-American, Asian, and Latino/Hispanic descent), with melanin affording protection against sun-induced damage.⁷  The different Fitzpatrick skin types are outlined in Table 1.2. Even among Caucasians, the gross appearance of photoaged skin of individuals with skin types I and II often differs from that of individuals with skin types III and IV. Skin types I–III have an increased risk of melanoma, keratinocyte cancers, and photoaging;^51,52  Fitzpatrick skin typing helps to predict the risk of these features.^53,54 

Until recently, extrinsic aging among Caucasians was an umbrella term for all features of UVR-induced changes affecting facial skin in particular. However, in the last few years, it has been shown both clinically and histologically that this is actually too simplistic. There are at least two distinct phenotypes of extrinsic aging among Caucasians. The first has been termed as Milian's citrine skin, now termed HP, and the second is the AP, telangiectactic phenotype.^8,9  The first phenotype is characterized by deep wrinkles, laxity, a leathery appearance, dyspigmentation, fragility, and impaired wound healing. The Favre Racouchot syndrome belongs to the HP subtype and is characterized by deep furrowing and nodular elastotic plaques on the peri-orbital and malar skin in combination with enlarged pilosebaceous orifices, comedones, and keratinous cysts.⁵⁵  The AP variant of photoaged skin reveals smooth, shiny skin with marked telangiectasia, focal depigmentation fine wrinkling and an increased prevalence of keratinocyte cancers and actinic keratosis.^9,56,57 

Fitzpatrick types I and II show AP skin changes with fine wrinkles and at times focal depigmentation and/or Poikiloderma of Civatte (hypopigmentation, hyperpigmentation, and telangiectasia),⁵⁷  dysplastic changes such as freckles, naevi, actinic keratosis, and keratinocyte cancers including basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs).⁵⁸  In contrast, people with skin types III and IV show HP responses such as tanning, deep wrinkles, coarseness, a leathery appearance of the skin, and lentigines.⁴⁶  The clinical differences are outlined in Table 1.3.

A study by Ayer et al. (2019) showed that 95% of AP subjects as compared to only 35% of HP were Fitzpatrick skin phototype I–II.¹⁰  Interestingly, 60% of AP participants had a history of keratinocyte cancers compared with none of the HP group. It is known that the risk of developing keratinocyte cancers is positively associated with cumulative UVR exposure from sunlight and artificial tanning lamps;^59,60  therefore, to ascertain whether all subjects had received similar cumulative UVR (as solar radiation), facial skin of all subjects was assayed for the occurrence of mitochondrial DNA damage^61,62  and it was found that similar levels of UVR-induced mitochondrial DNA damage were detected, irrespective of photoaging phenotype. Thus, all subjects had received similar lifetime cumulative doses of UVR.

The incidence of keratinocyte cancers has been increasing rapidly over the past half century,^63,64  and there are several reports of an association with AP.^{48,58,65–68}  Patients treated for facial BCCs rarely present with deep coarse wrinkling – commonly defined as a marker of significant sun exposure.⁶⁷  Similarly, individuals with Fitzpatrick phototypes I–II are more likely to develop BCCs or SCCs than those who always tan (Fitzpatrick phototype IV);^58,67,69  findings that are consistent with our AP cohort. The risk is further positively associated with male gender.^70,71  In agreement with these studies, Ayer et al. found the incidence of keratinocyte cancers for their AP cohort was twofold higher in men than women.

Histologically, the early stages of photodamage are marked by a loss of oxytalan fibres and fibulin-5 at the DEJ.^72,73  Chronic exposure to UVR, however, reveals more profound damage to the skin's architecture. A loss of mature dermal collagen occurs; anchoring fibrils containing collagen VII which provide stability of the DEJ are markedly reduced in number.⁷⁴  Glycosaminoglycans and dystrophic elastotic material are deposited in the deep dermis as revealed by immunohistochemical staining for severely disorganized tropoelastin and its associated microfibrillar components.⁷⁵  Fibrillin-rich microfibrils (FRMs) appear severely truncated and are depleted in the upper dermis adjacent to the DEJ.⁷³ 

Resident fibroblasts of the dermal connective tissue have characteristic features including a stellate phenotype.⁷⁶  Increased numbers of mast cells, mononuclear cells and neutrophils have been reported in murine photoaged skin, in contrast to hypocellularity in intrinsically aged skin.⁷⁷ 

A number of photoaging biomarkers have been investigated in the context of the histological changes that occur in extrinsic aging.

Elastosis is a histological characteristic of dermal photoaging, and refers to changes in both the quality and quantity of elastic fibres.⁷⁸  In severely photoaged skin, disorganized elastotic material is deposited within the reticular dermis^79–81  replacing the normal elastic fibre architecture. The remodelling of the matrix is associated with a reduction in tissue elasticity,⁸²  which is defined as the percent of recovery after vertical deformation, measured with a tonometer. Figure 1.1 illustrates the effects of photoexposure on the elastic fibre network in HP skin.

Statistically significant differences in elastic fibres have now also been outlined in the literature^10,83  when comparing AP facial photoaging to HP facial photoaging. These data showed that AP male facial skin had a significantly lower percentage of solar elastosis than HP facial skin in both male and female volunteers; the histological differences are shown in Figure 1.2. These histological changes most notably were not seen in photoprotected sites taken from the same subjects.¹⁰ 

These differences are thought to either be a result of UV-induced proteolytic activity on mature elastin fibres causing degradation, or the de novo deposition of elastic material that is not assembled into elastic fibres.⁸⁴  It is also possible that both processes occur in tandem. It is known that exposure to UVR results in the remodelling of elastin fibres and the FRMs network within the papillary and reticular dermis. Elastin, FRMs, and other components of the extracellular matrix (ECM), are substrates for a range of proteases.⁸⁵  For example, FRMs are proteolytically cleaved by matrix metalloproteinases (MMPs) −2, −3, −9, −12, and −13^86–90  and by the serine protease neutrophil elastase.⁹¹  It is now recognized that an increase in protease activity within the extracellular space occurs in response to UVR exposure and the downregulation of tissue inhibitors of metalloproteinases (TIMPs) causes remodelling of the ECM within photoaged skin.^92,93 

Sherratt et al. (2010) proposed that the exposure of elastic fibre components, rich in UVR-chromophore amino acids, may provide an alternative in vivo catabolic pathway. It has been suggested that the location of these elastic fibre components are within the DEJ, and that their longevity and chemical composition may predispose these structures to both direct and indirect degradation by UVR in vivo. More importantly, the proposed selective multi-hit model of photoaging proposed a mechanism by which increased transforming growth factor (TGF)-β signalling may drive elastosis in photodamaged skin.⁹⁴ 

FRMs are insoluble polymers that provide a template for elastin deposition,⁹⁵  they contain UV-chromophore/reactive oxygen species (ROS)-susceptible amino acid residues which undergo extensive remodelling following exposure to UVR as shown in Figure 1.3.

Studies suggest that an acellular pathway may play a key role in photoaging by mediating the selective, UV-induced degradation of extracellular proteins which are rich in amino acid UV chromophores,^96,97  in addition to the action of proteases. FRMs have been shown to be significantly truncated and depleted in the upper dermis at the DEJ of photoaged skin.⁷³  It is now also known that there are statistically significant differences in FRMs when comparing AP males and HP male and female facial photoaging (Figure 1.4). These changes were not detected in photoprotected skin taken from the same individuals.¹⁰ 

FRMs are known to regulate the bioavailability of TGF-β within the ECM;^98,99  TGF-β is important for matrix remodelling and the upregulation of elastin gene expression in human skin fibroblasts.^100,101  This is achieved through several cell-specific mechanisms.¹⁰²  TGF-β is also important in driving elastogenesis in a number of different pathological conditions including pulmonary hypertension, pulmonary fibrosis, and solar elastosis.^103–105  It is a known activator of fibroblasts in fibrosis and is an upstream regulator of connective tissue growth factor (CTGF), which stimulates matrix production.¹⁰⁶  The photodamaged tissue microenvironment shows evidence of proteolytic degradation.^73,80  Proteolytic cleavage has also been shown to activate latent ECM-bound TGF-β1,¹⁰⁷  which may in turn drive the aberrant ECM remodelling in solar elastosis.⁸⁰  Activated fibroblasts, adjacent to the elastotic material, suggest that de novo deposition of matrixes may contribute to the extensive remodelling of the ECM in photodamaged skin.^108,109  The ability of TGF-β to regulate elastin fibre assembly is therefore likely to be a significant contributory factor in the accumulation of elastotic material and in turn the clinical appearance of skin wrinkling.

Degradation of fibrillin also has an effect on TGF-β signalling, as highlighted in Marfan syndrome, a prototypic fibrillinopathy, which is caused by misfolding of fibrillin-1. It has been shown that a specific fibrillin-1 degradation product can directly facilitate TGF-β activation from latent TGF-β binding proteins (LTBPs).^110,111  UVR acts on cellular and extracellular chromophores to generate oxidative stress and upregulates protease expression, which are thought to target the oxytalan fibres within FRMs in the DEJ and potentially increase TGF-β activation.^84,97 

A mouse model of Marfan syndrome shows that an upregulation of the TGF-β pathway is partly responsible for the phenotype.^92,107  This phenotype can be rescued by drug sequestration of TGF-β. Furthermore, in vitro studies have shown that a central recombinant fibrillin fragment acts on cells to induce further protease expression and may increase TGF-β signalling.^110,111  This fibrillin/TGF-β axis has also been proposed to drive the excessive generalized ECM deposition observed in SCCs,^107,112  and may also be involved in solar elastosis.

It has been speculated that rather than simply being a result of photodamage, it is possible that the de novo deposition of the dense elastin-rich matrix in photodamaged skin may also serve a protective role. Chronic UVR exposure is reported to be the major contributory factor in skin carcinogenesis. TGF-β is a pleiotropic cytokine that is known to promote cancer growth and drive cellular processes in carcinogenesis such as metastasis.^113–115  Studies have shown that increased levels of TGF-β1 expression also occur in human cutaneous SCCs.¹⁰³  There is significant evidence that the photodamaged tissue microenvironment is rich in protease activity leading to TGF-β activation.¹¹⁶  This enzymatically reactive tissue microenvironment is, to some degree, beyond the regulatory control of the cell because these proteases have been shown to reside and are active within the extracellular space.^117,118  Elastin acts a substrate for many of these proteases. The de novo deposition of a dense elastin-rich matrix by the cell may therefore reduce the aberrant TGF-β signalling by effectively acting as a preferential substrate for these enzymes over the large latent complex (LLC). As keratinocyte cancers occur more frequently in AP which lacks dermal elastosis, it is possible that the elastotic material within the dermis may confer a protective role against carcinogenesis in photodamaged skin by quenching TGF-β activation. If this hypothesis was true, it would follow that AP skin may have greater levels of TGF-β activity due to the lack of elastotic material, and thus higher numbers of keratinocyte cancers.

The association between solar elastosis and cumulative photoexposure has been consistently reported across sunlight environments from high levels in Queensland¹¹⁹  to low levels in New Hampshire¹²⁰  across a wide latitude range at 27°S to 43°S.¹²¹  Chronically sun-exposed individuals show a significant increase in the expression of cutaneous elastin.¹²²  Sachs et al. (2019) showed in their study that HP individuals were characterized histologically as having more widespread elastotic damage than AP individuals.⁹  Clinically, this correlated with increased skin wrinkling. Their study alluded to solar elastosis having a negative correlation with keratinocyte skin cancers development; now confirmed by Ayer et al. (2019).¹⁰ 

The major components of the ECM in the dermis are fibrillar collagens.¹²³  They are composed mainly of glycine, proline, hydroxyproline and are two of the strongest proteins in nature.¹²⁴  Collagen makes up to 70–80% of the dermal weight. Currently there are 28 distinct types of collagens encoded by 44 different genes in the human genome.¹²⁵ 

Types I, II, III, V, and IX are fibril-forming collagens.¹²⁶  The most common collagens found in the skin are the fibrillar collagens, types I (70–75%), III (18–21%) and V (2–4%), and the basement membrane localized types IV and XVII, and type VII which forms anchoring fibrils.¹²⁷  The ratio of type I to type III collagens within the skin is affected by aging.¹²⁸ 

Type III collagen is also known as foetal collagen because of its abundance in foetal tissues.¹²⁸  Consequently, the content of types I and III as well as the type I : III ratio in normal skin differs according to age. In adult skin there is a greater production of type I collagen, which results in a final ratio of 6 : 1 type I : type III collagen.¹²⁹  The lowest levels of type I and type III collagen and the highest ratio of collagens I : III are observed in the elderly age group.¹³⁰  It is known that there is a 40% decrease in the content of type III pro-collagen in sun-damaged skin as compared to non-photo-exposed skin.¹³¹  Facial skin biopsies have shown noticeable changes in collagen from the fifth decade, and indeed by the eighth and ninth decades only sparse amounts of collagen I and III were seen Both collagens are under UV stress.¹³²  Collagen I photodegradation has been implicated in skin wrinkles and it is possible that it could play a role in skin cancers.^133,134  UVR appears to accelerate collagen damage in extrinsic aging.

Type VII collagen and laminin-332 are essential components of the DEJ, anchoring the epidermis to the dermis.¹³⁵  Both collagen VII and laminin-332 are known to decrease with age¹³⁶  and a number of studies have found a reduction of collagen VII mRNA and protein expression within photodamaged skin.^74,137  The loss of collagen VII and the Lama3 subunit of laminin 332 have been implicated in cutaneous SCC invasion.^138–140 

Collagen VII is reduced in the base of a wrinkle as compared to its flanks.^74,141  This may contribute to the appearance of the flattened DEJ, due to weakening of the attachments between the epidermis and dermis and is significantly reduced in AP male facial skin compared to HP facial skin. Figure 1.5 illustrates the histological differences. These differences are not present in the photoprotected skin taken from the same participants in this study.¹⁰ 

The importance of anchoring fibrils to skin function is exemplified clinically by inherited skin fragility which comprises a spectrum of disorders, mainly epidermolysis bullosa (EB). EB is characterized by mechanical-induced blistering and erosions within the skin and mucosal membranes as a consequence of mutations in genes encoding proteins involved in intra-epidermal or dermal–epidermal adhesion.¹⁴²  Although blistering is not a characteristic feature of photoaged skin, it has been described in a proportion of patients following chronic exposure to sunlight or sunbeds.¹⁴³ 

A high proportion of recessive dystrophic epidermolysis bullosa (RDEB) patients carry a germ-line mutation in the collagen, type VII, alpha1 (COL7A1) gene.¹⁴⁴  The deficiency in anchoring fibrils leads to severe blistering, skin atrophy, and scarring. Patients with the severe generalized subtype are at a much higher risk of SCCs.^76,77,128  Data from the National EB Registry in the USA have shown that by the age of 45, approximately 85% of all patients with a severe generalized subtype of EB developed at least one cutaneous SCC.¹⁴⁵  The mechanisms by which type VII collagen defects cause SCCs are still undetermined. However, Martins et al. (2009) have postulated that loss of collagen VII correlates with decreased involucrin expression in vivo. It is possible that a loss of collagen VII may increase expression of the chemokine ligand receptor CXCL10–CXCR3 and downstream-associated phospholipase C gene signalling, which could in turn contribute to the increased metastatic potential of SCCs in the scenario of reduced or absent collagen VII expression.¹⁴⁰  Ng et al. have also shown that matrix composition in patients with RDEB may provide an optimal environment for the development of SCC, and that collagen VII directly regulates proteins secreted by dermal- and cancer-associated fibroblasts.¹⁴⁶  It is possible that a significant reduction in collagen VII in AP males could be pathological, particularly as there was also a significant difference detected between AP photoexposed and photoprotected skin. No differences of Lama3 were noted between AP and HP skin, however.

CD44 is a polymorphic proteoglycan which functions as the principal cell surface receptor for hyaluronate. Hyaluronic acid (HA) is a glycosaminoglycan (GAG) which is able to bind and retain water molecules. One of the most marked histological changes in aging skin is the substantial decrease in epidermal HA, despite it still being present in the dermis.¹⁴⁷  Thus, the epidermis loses its ability to bind and retaining water molecules leading to a loss of skin moisture.¹⁴⁸ 

Photoaging results in abnormal GAG content and distribution with diminished HA and increased levels of chondroitin sulfate proteoglycans.¹²²  CD44 is involved in cell to cell interaction, cell adhesion and migration. It can also interact with other ligands such as collagen. In keratinocytes, CD44 fixes the molecules of HA. When it is activated, it produces a downstream cascade of reactions necessary for the correct functionality of these cells. The interaction between this receptor and its ligand also promotes the synthesis of necessary lipids and structures so the permeability and function of the epidermal barrier is adequate.¹⁴⁹ 

In the dermis, CD44 acts by binding the components of the ECM to fibroblasts which strengthen tissue cohesion. A defect in this receptor can cause an accumulation of HA on the surface of the dermis, a loss of elasticity, and an alteration of tissue repair.¹⁵⁰  In addition, CD44 is essential for the degradation and subsequent regeneration of hylauronate at both extracellular and intracellular level.¹⁵¹ 

UVR decreases the expression of CD44 receptor and also HA in the epidermis.¹⁵²  It has been reported by comparison of photoexposed and photoprotected human skin tissue specimens, obtained from the same patient, an increase in the expression of HA of lower molecular mass in photoexposed skin, as compared with photoprotected skin. The reported increased expression of lower molecular mass HA in photoexposed skin was associated with a significant decrease in the expression of ic HA Synthase-1 (HAS-1) and an increased expression of hyaluronidases (HYAL-1, -2 and -3).¹⁵²  Furthermore, the expression of the HA receptor CD44 was significantly downregulated in photoexposed, as compared with photoprotected skin. These findings indicate that extrinsic skin aging is characterized by distinct homeostasis of HA.¹⁵⁰ 

The defective functionality of the receptor also leads to dermatoporosis in which skin has lost its protective mechanical function. Abundance of CD44 was measured in both AP and HP skin, with no differences noted between gender, phenotype, or compared to photoprotected sites.¹⁰ 

A single exposure to UVB radiation causes cutaneous changes including erythema,^153,154  vascular hyper-permeability,¹⁵⁵  dilation of dermal blood vessels,¹⁵⁶  and epidermal hyperplasia.^88,157  Acutely, UV exposure stimulates angiogenesis following induction of vascular endothelial growth factor (VEGF) upregulation and thrombospondin-1 (TSP-1) downregulation in the human epidermis.¹⁵⁵  Studies suggest that the balance between VEGF and TSP-1 expression is disturbed, and this in turn leads to a UVB-induced angiogenic switch, facilitating the infiltration of elastase-producing leucocytes and consequently cutaneous photodamage. However, the true underlying mechanisms of vascular changes in photoaged skin are not clear.¹⁵⁸ 

Furthermore, angiogenesis and lymphangiogenesis have received considerable interest because of their role in promoting cancer metastasis.^159–162  Vascular remodelling is also an important feature of acute and chronic inflammatory disorders including chronic airway disease,¹⁶³  inflammatory bowel disease,¹⁶⁴  atherosclerosis,¹⁶⁵  and chronic dermatoses such as psoriasis.^{104,166–168}  The levels of VEGF-A are known to be elevated in inflamed tissue.^92,166,169  VEGF has been found to be upregulated in skin conditions that are characterized by epidermal hyperplasia and dermal angiogenesis.^170,171  AP facial photoaging has significantly increased vasculature as measured by von Willebrand Factor (vWF) when compared to HP facial photoaging (Figure 1.6).

The defining clinical characteristics of AP are erythema and telangiectasia,¹⁷²  but little has been reported objectively. It is unknown if the erythema and telangiectasia are more clinically apparent due to their location superficially in the skin, which becomes more pronounced due to skin thinning. Sachs et al. (2019) previously showed that telangiectasia in AP skin was severe in 32% of cases compared to only 4% in the HP facial skin.⁹  AP photoaging is characterized by transient and non-transient erythema, a lateral distribution of erythema and telangiectasia, neurogenic mast cell activation, and some MMP-induced matrix remodelling.¹⁷²  These data suggest that photoexposure increases the development of blood vessels in the AP phenotype and to a lesser degree in HP facial skin. Helfrich et al. have demonstrated histologically that AP photoaged dermis contains dilated blood vessels.¹⁷²  The photoprotected buttock skin had reduced vasculature compared to the facial skin in both phenotypes, suggesting that that the observed neovascularization is a consequence of photoexposure. Previous studies have shown that photoprotected buttock skin has a reduced vasculature as a consequence of chronological aging.^45,173  This suggests that an increase in the numbers of blood vessels in AP skin could be pathological and that the clinical appearance of the AP phenotype is a direct consequence of increased vasculature.

Epidermal thinning has long been established as natural sequela of aging, and is known to be accelerated by cumulative photoexposure.^{15,141,174,175}  Overall, epidermal thickness has been reported to decrease at about 6.4% per decade, from 77 ± 7 µm in the young to 69 ± 10 µm in the older population,^176,177  and decreases occur more quickly in women than in men.^160,178  Normal reported values for epidermal thickness vary depending on anatomical site. Facial epidermal thickness in the over 50s has not been widely reported. However, El-Domyati et al. (2002) measured the living layers of facial skin and found that individuals between the ages of 50 and 90 years of age had a greater mean facial epidermal thickness compared to the abdominal photoprotected skin from these same individuals.¹⁸³  However, measurement techniques differ considerably from study to study, with some measuring living layers of the skin and some including or excluding the rete ridges. There are differences in epidermal thickness between AP and HP facial photoaging. AP facial photoaging has significantly increased epidermal thickness when compared to HP facial photoaging, and further gender stratification showed that AP males had a significantly thicker epidermis than AP females.¹⁰  No differences were reported in DEJ convolution between the two phenotypes.

The finding of increased epidermal thickness in AP skin is counterintuitive given that the skin looks thinner than in HP skin. However, it could be that the telangiectasia in AP skin give the factitious appearance of translucency. It is also possible that thinning may occur at the level of the stratum corneum as it was only the living layers of the epidermis that were measured. HP skin clinically appeared thicker and leathered and thus intuitively led to the hypothesis that HP skin would possess a thicker epidermis. However, it is reported in the literature that the stratum spinosum is generally thinner at the bottom of a wrinkle.¹⁴¹  As HP skin is deeply wrinkled, there may be marked thinning at the level of the stratum spinosum, which may also account for the thinner epidermis of HP group.

Epidermal thickness is affected by age, gender, skin type, vascular supply, smoking habits, and body site.¹⁷⁶  This could account for the differences between AP males and females. Photoprotected skin is thought to decrease in thickness by up to 50% between the ages of 30 and 80 years.^159,179  In a study by Sandby-Moller et al., the reported value for the thickness of the cellular layers of buttock epidermis was 81.5 µm.¹⁷⁷  The skin sampled was obtained from 71 volunteers of Nordic ancestry, with an age range between 20 and 68 years; there was no further information on which measurements corresponded to which participant.

Studies have correlated flattening of the dermal–epidermal interface with intrinsic aging.^13,161  These changes are thought to be more modest, however,¹⁸⁰  than the rete ridge effacement commonly noted in photoaged skin.^181–183  Ayer et al. (2019) demonstrated that there were no significant differences in DEJ convolution in photoexposed or photoprotected AP or HP cohorts with effacement of the rete ridges at both sites.¹⁰  This suggests that flattening of rete ridges was predominantly a feature of intrinsic aging, which may have been accelerated by sun exposure.

Assessing the severity of cutaneous photodamage and its response to treatment has often been a challenging and often impractical consideration for most dermatologists. It requires either substantial experience in the area, or recourse to high-quality, standardized, baseline photographs. Photonumeric scales have consistently shown superiority over descriptive equivalents, and have the advantage of providing a consistent visual frame of reference, thus minimizing variability in perception and subjectivity. A study performed over 25 years ago developed and tested a photonumeric scale to assess HP facial photodamage (Figure 1.7).⁴⁶ 

It was found that the photonumeric model was superior at evaluating skin changes than the standard descriptive scale used at the time. A further photonumeric scale has now been developed to objectively assess AP photodamage, which is associated with a greater risk of developing keratinocyte-derived skin cancers (Figure 1.8).⁶⁵ 

Photonumeric scales demonstrate superiority and can be used outside clinical settings. They have a role in categorizing groups of photoaged subjects prior to treatment with skin repair agents, thereby obtaining consistent and uniform groupings of subjects, e.g. those with mild to severe photodamage. This would allow greater reliability among centres involved in photodamage studies and enable independent regrading of good-quality study photographs.

UVR exposure and resultant photoaging is an increasing challenge among the general population. Compliance with photoprotection continues to be a health promotion concern, particularly in view of the increasing incidence of keratinocyte cancers melanoma. The guidelines developed by the US Preventive Services Task Force suggest that avoiding direct sunlight by staying indoors or in the shade, or by wearing photoprotective clothing, is the most effective measure for reducing exposure to UVR. However, there are no randomized trials of sun avoidance to prevent photoaging. The studies outlined in this chapter have looked at photoaging markers and demonstrated at a histological level the effects on the skin. With this is mind, future studies are required to elucidate underlying mechanisms and future treatment modalities to retard and ultimately prevent photoaging.