C H A P T E R

2Skin Aging and Oxidative Stress

John M. StarrCentre for Cognitive Aging and Cognitive Epidemiology, Edinburgh, United Kingdom

Robert J. StarrSchool of Medicine and Dentistry, Polwarth Building, Foresterhill, Aberdeen, United Kingdom

List of AbbreviationsBCC basal cell carcinomaDNA deoxyribonucleic acid8-OHdG 8-hydroxy-2′-deoxyguanosineUV ultraviolet light

INTRODUCTION

The skin is one of the largest organs of the human body. Like some other organs, it is directly exposed to a number of environmental toxins, but is almost unique in being exposed to the effects of sunlight. Skin aging can therefore be considered in terms of (1) intrinsic aging processes common to cells throughout the body, (2) the impact of chronic exposure to various environmental toxins, and (3) what is termed ‘photoaging’, the effects of exposure to UV light. Fortunately, compared to all other organs, the skin is relatively easy to gain access to for the study of cellular processes.

THE STRUCTURE OF HUMAN SKIN

The human skin is organized into two major layers, the deeper dermis and the superficial epidermis. The epidermis can be divided into five further layers, from most superficial to deepest:

• stratum corneum • stratum licidum • stratum granulosum • stratum spinosum • stratum basale

Aginghttp://dx.doi.org/10.1016/B978-0-12-405933-7.00002-0

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The stratum basale consists of columnar cells, kera-tinocytes, which divide and move gradually through subsequent layers to reach the stratum corneum. As they move towards the surface, the cells become gradually more and more flat. The stratum corneum consists of dead cells that are shed every 2 weeks. In addition to keratinocytes, there are three other types of specialized epidermal cells that make up only around 5% of the epidermal cell population. These are:

• melanocytes that produce the pigment melanin • the Langerhans’ cells that have primarily immune

functions • Merkel’s cells found in touch-sensitive areas of the

skin and associated with cutaneous nerves

Epidermal thickness varies up to 30-fold, from 0.05 mm on the eyelids to 1.5 mm on the palms and soles.

The thickness of the dermis also varies from around 0.3 mm on the eyelids to 3 mm over the back. The dermis has a far more complex structure than the epidermis. In general it has two layers, the more superficial papillary layer and the deeper reticular layer. But in addition it contains collagen, elastic tissue and reticular fibers that occur in both layers. The dermis is also penetrated by blood vessels and nerve cells, the former reaching super-ficially to supply the stratum basale of the epidermis. There are specialized nerve structures called Meissner’s and Vater-Pacini corpuscles that are involved with light touch and pressure sensation. Hair follicles can be found throughout almost all of the human dermis, with the erector pili muscle attached to each follicle. Each follicle also may have sebaceous and apocrine glands associated with it. Finally, also widespread throughout the dermis are eccrine glands that produce sweat.

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The dermis and the epidermis are bound togethat a basement membrane. The stratum basale cells aattached to this membrane via anchoring filamenof hemidesmosomes. The papillary cells of the dermattach to the membrane via anchoring fibrils made collagen.

Below the dermis lies the so-called subcutaneous tisue that contains larger blood vessels and nerve celalong with adipocytes; loss of this tissue, rather than anintrinsic changes in either the dermis or epidermis, cachange human appearance and result in changes assocated with human aging. This is a very important consieration when choosing indices of skin aging because nall measures will necessarily relate entirely to changoccurring within the skin itself.

MEASURING SKIN AGING

The most common non-invasive method to measuskin aging is the counting of specific features from higquality photographs, usually of the face. Guinot ancolleagues validated such a scale in 361 white womeaged 18 to 80 (mean age 43.5) years living in FranceThey evaluated 62 facial skin characteristics on ordnal scales and found that only 33 of these were signifcantly associated with chronologic age. Factor analysallowed them to exclude nine redundant items, leavinthem with 24 items that they split into six groups by prsumed etiology, but finally recommended using the totscore. Allerhand and colleagues applied 16 of these scaitems to photographs of 314 men and women of meaage 83.24 (range 82.04 to 84.57) years.2 They identifie10 items that had good inter-rater reliability (Table 2.

TABLE 2.1 Skin Aging Items and Their Relationship with Three Extracted Factors. ++ Represents a High Factor Loading, +Represents a Moderate Factor Loading

Pigmented Spots Wrinkles Sagging

Pigmented spots cheek ++ +

Pigmented spots forehead

++

Fine lines forehead +

Wrinkles cheek ++ +

Wrinkles under eyes +

Wrinkles upper lip ++

Furrows between eyebrows

+

Nasolabial folds +

Crows feet ++

Bags under eyes

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AND OXIDATIVE STRESS

er re ts is of

s-ls y n i-

d-ot es

re h-d n .1 i-i-is g

e-al le n d 1)

and performed confirmatory ordinal factor analysis with an oblique structure that proved to be consistent with the factor structure derived by Guinot and colleagues in their younger, female-only sample.

The three factors were best described as representing the number of pigmented spots, wrinkles and sagging. These last two factors were strongly correlated with each other (r = 0.7), but far less strongly with the factor repre-senting pigmented spots. Interestingly, the ‘bags under eyes’ item did not have a loading >0.3 on any of the factors. In summary, the key finding from both studies using a facial skin aging scale is that skin aging is multi-dimensional. This multi-dimensionality may relate to the three major pathways to skin aging outlined above in the Introduction. It is unclear whether the same factors would summarize skin characteristics from parts of the body that are not exposed to sunlight on a regular basis.

As noted in the Introduction, skin is easily acces-sible for tissue sampling to examine the morphologic changes that occur with age in the dermis and epider-mis. These changes can be measured from prepared slides, and some gross changes, such as skin thickness, can be measured by ultrasound. Under light microscopy there is progressive flattening of the epidermal junc-tion, which is more undulating in youth, as humans age. This flattening results in a general thinning of the epidermis in older adults and also an increased tendency for epidermal–dermal shearing. Dermal thickness in non-light-exposed areas also decreases with increasing age and correlates with reduced collagen content.3 This change reflects fibroblast function, but the dermis is a complex structure, and age-related changes in embed-ded blood vessels and cutaneous nerves also occur that are similar to changes in these structures seen elsewhere in the body. More specifically for skin, sebaceous glands produce less sebum from around 20 years of age so that the skin of older adults is more likely to be dry.

CELLULAR CORRELATES OF SKIN AGING

As noted above, the epidermis is a high-turnover tis-sue and this predisposes it not only to senescent effects, but importantly also to the generation of neoplastic cells. As the keratinocytes move out from the stratum basale they undergo proliferation, differentiation and finally apoptosis. In older people, replicative senescence, where cells remain viable and metabolically active but not capa-ble of further replication, is more common. Langerhans’ cells provide frontline immune responses to present-ing antigens, migrating to local skin- draining lymph nodes where they facilitate the presentation of antigen to T-lymphocytes. Older adults have fewer Langerhans’ cells4 and those present have impaired migratory

STRESS AND AGING

TRInSIC SkIn AgIng 17

OxIdATIvE STRESS And In

properties.5 These observations have implications for increased susceptibility to skin infections and neoplasia in older adults.

The fibroblasts of the dermis are probably the most studied human cell type with regard to cellular senes-cence. Typical features are increased DNA double-stand breakage, telomere dysfunction and heterochromatini-zation of the nuclear genome which indicate that more than 15% of cells are in a senescent state in old age.6 As expected, apoptotic cell death is increasingly likely with an increasing number of fibroblast divisions and is asso-ciated with impaired mitochondrial function.7

OXIDATIVE STRESS AND INTRINSIC SKIN AGING

There are limited in vivo data from humans suggest-ing that oxidative stress is associated with skin aging. An example is the finding that elevated serum 8-hydroxy-2′-deoxyguanosine (8-OHdG, a measure of oxidative DNA damage) occurs in older adults with more pigmented spots or facial sagging.2 It is possible that collagen frag-mentation, which is a feature of skin aging, increases serum 8-OHdG levels.8 Another possibility is that there is some ‘common cause’ that drives both oxidative stress and skin aging independently. However, the redox sta-tus of a cell is a very basic influence on a whole range of processes and the only characteristics that might be considered more fundamental are genetic and epigen-etic factors. But telomere length, the major indicator of genetic aging, is thought to be influenced by oxida-tive stress,9 so invoking genetic factors as a ‘common

TABLE 2.2 key Cellular Processes that Change with Increasing Levels of Oxidative Stress

Low oxidative state Normal status for most organelles, although some, such as the endoplasmic reticulum, may prefer a higher oxidative resting state to facilitate protein folding and disulfide bridge formation.

Mildly increased oxidative state

Mild increases in intracellular Ca2+ levels and increased phosphorylation.

Moderately increased oxidative state (oxidative stress)

Further increase in intracellular Ca2+ levels and release of Fe2+, Cu2+ and other transition metal ions. DNA damage may occur. Cell cycle halts to allow repair of DNA damage and antioxidant systems kick into action.

Highly oxidative state Mitochondrial damage occurs. p53-related DNA damage induces apoptosis.

Very highly oxidative state (severe oxidative damage)

Shut down of caspases halts apoptosis leading to necrosis and release of transition metals etc. that damage surrounding tissue.

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cause’ would produce a paradoxical model. Given this, it is most parsimonious to consider a causal relation-ship between oxidative stress and skin aging with by far the biggest weight of evidence indicating that oxidative stress drives skin aging and not vice versa.

The skin and the lungs are the only organs substan-tially exposed to atmospheric oxygen. Aerobic metabo-lism draws on the availability of O2 to increase energy generation. Aerobic metabolism occurs in the mitochon-dria and generates reactive oxygen species. It is an excess of these species leaking out of the mitochondria that results in oxidative stress. Table 2.2 summarizes some key cellular processes that vary according to redox sta-tus. Under normal conditions, atmospheric oxygen can supply the upper skin layers to a depth of 0.25–0.40 mm, which is the entire dermis and epidermis of the eyelids,10 but only about one quarter of the depth of the palms and soles. Uptake in normal skin is unaffected by age,10 but because the skin is thinner in older adults, more of the O2 required is derived from the atmosphere rather than from the dermal blood supply. Those living at high altitude are more dependent on blood supply and are at increased risk of age-related skin changes because of higher UV light exposure (see below).

As outlined above, collagen is a key component of the human dermis, and the release of transition metals that occurs with increasing oxidative stress (Table 2.2) leads to metalloproteinase-1-induced collagen fragmen-tation.8,11 Oxidative stress also increases the inversion of L- to D-form aspartyl residues in elastin typical of aging skin and related to its reduced elastic properties.12 Hence, along with cellular changes resulting from oxidative stress, important changes to the skin tissue matrix also occur.

There are several cellular antioxidant defense systems that are present throughout the human body. Those enzymatic systems that are most important in the skin are superoxide dismutase,13 which helps to combine the superoxide anion with two hydrogen ions to pro-duce hydrogen peroxide and oxygen; catalase,13 which catalyzes the breakdown of hydrogen peroxide to water and oxygen; and the glutathione system.13 There are two main glutathione enzymes present in skin cells: glutathi-one peroxidase, with an enzyme activity in the epider-mis 62% of that in the dermis, and glutathione reductase, with an enzyme activity level in the epidermis 32% of that in the dermis. Other, less active, antioxidant systems include thioredoxin reductase14 and methionine sulfox-ide reductase.15 In addition to these enzymes, there are non-enzymatic compounds in the skin that have antioxi-dant properties (Table 2.3).

An increased number of pigmented spots is a skin aging characteristic associated with oxidative stress.2 Nitric oxide radicals derived from keratinocytes pro-mote pigmentation by inducing melaninogenic enzymes

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tyrosinase and tyrosinase protein-1.16,17 Ascorbic acid eliminates nitric oxide radicals and has an inhibi-tory effect on tyrosinase. There are various forms of tocopherol (vitamin E) with γ-tocopherol superior to α-tocopherol in its ability to inhibit melanogenesis by scavenging nitric oxide radicals.18 Various skin cancers occur more commonly in older people. This is largely due to UV exposure (see below), but one study found that a single nucleotide polymorphism in Nitric Oxide Synthase 1 oxidative stress gene increased the risk of malignant melanoma,19 indicating that oxidative stress may play a part in predisposing skin cells to neoplasia. However, the exact role may differ between melanoma and non-melanoma skin cancer. In the latter it appears as if a reduction in antioxidant defense systems is the predisposing factor rather than increased levels of oxida-tive stress.20

ENVIRONMENTAL EXPOSURES ASSOCIATED WITH SKIN AGING

A fad for using arsenic-containing tonics in chil-dren in the 1930s saw a subsequent increase in people developing multiple basal cell carcinomas (BCC). In fact, even at relatively low levels, arsenic increases the risk of BCCs.21 Arsenic predisposes to squamous cell cancer as well as to BCC, but not to malignant mela-noma.22 Arsenic can increase oxidative stress by acting as an electron carrier so that transition metals can cycle between oxidative states.23 In addition, methylated arse-nic can damage DNA directly and thus predispose to malignancy (see ref. 23 for a full review) and can induce apoptosis through the mitochondrial pathway. Notably, chronic arsenic exposure decreases antioxidant enzyme activity,23 especially superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, all important in skin cells. This most likely explains the differences in arsenic risk between melanoma and non-melanoma skin cancer.

Cigarette smoking is the most widely recognized environmental source of carcinogens. It is associated with risk of squamous cell cancer of the skin, but not with risk of BCC.24 Smoking does not increase the risk

TABLE 2.3 non-Enzymatic Compounds in the Skin that Have Antioxidant Properties

• Ascorbic acid (vitamin C) • Uric acid • Glutathione • Tocopherol (vitamin E) • Ubiquinol • Retinoids • β-Carotene • Protein thiols

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XIDATIVE STRESS

of melanoma, in fact, if anything, it may reduce sus-ceptibility.25 This limited impact of smoking on age-related neoplasia is in contrast with its major impact on skin aging.26 The molecular basis of the premature skin aging effect of smoking is in the process of being elucidated. Smokers have higher concentrations than non-smokers of matrix metalloproteinase-1 mRNA in the dermis27 and, as previously noted, this enzyme leads to increased collagen fragmentation and is, itself, influenced by oxidative stress.8,11 There is clear evi-dence that smoking induces oxidative stress in other tissues, such as the heart.28 How much of this effect is due to nicotine, which influences nitric oxide synthase levels, and how much to other moieties within cigarette smoke is unclear. Cigarette smoke contains free radi-cals, which may be able to diffuse into the skin from the atmosphere surrounding a smoker. This may explain, in part, why there is such a differential effect on facial skin aging.

If cigarette smoking can have a local effect on skin due to it containing free oxygen radical species, it is possible that other air pollutants may have this effect also. Ambient particulate matter in the nanosize range can cause oxidative stress because the large surface area to volume ratio of these particles makes them highly reactive towards biologic structures, and they may also carry a variety of transition metals that local-ize inside mitochondria, inducing oxidative stress. In addition, ambient particulate matter in the nanosize range may carry polycyclic aromatic hydrocarbons that are converted to quinones which, like arsenic, facilitate redox cycling and thus worsen oxidative stress. Skin aging was assessed in the SALIA study, which com-prised 400 women residing either in industrialized cit-ies of the Ruhr or in rural Borken, and traffic pollution correlated positively and significantly with the number of pigmented spots and with facial sagging character-istsics.29 These relationships persisted after adjustment for potential confounding variables and would be con-sistent with skin aging changes related to oxidative stress.2

Less established, but biologically plausible, is a role for copper as an environmental toxin that may cause skin aging. Trace amounts of copper are, of course, essential for health, and failure to absorb copper results in the widespread abnormalities seen in Menke’s dis-ease, including brittle hair due to defective collagen and elastin polymerization. However, experimental data in dermal fibroblasts show that higher levels stimulate metalloproteinase-1 with all its consequences for col-lagen,30 and it may be that it also affects mitochondrial function.

A major environmental determinant of both skin can-cer and skin aging is UV light (listed in Table 2.4). It is of such importance that it requires a section of its own.

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TABLE 2.4 Summary of the Effects of known Environmental Exposures on Skin Aging and Skin Cancers

Environmental Exposure Effects on Skin Aging Association with Skin Cancer

Cigarette smoking Direct effects of free radicals from cigarette smoke absorbed through the skin.Indirect effects via nitric oxide synthase and other possible pathways.Increased collagen fragmentation.

Increases basal cell carcinoma risk, but not squamous cell carcinoma or melanoma risk.

Ambient particulate matter Nanosize particles highly reactive with cell membranes.May also carry transition metals and polycyclic aromatic hydrocarbons that are converted to quinones, facilitating redox cycling.

No associations identified.

Arsenic Can act as an electron transporter for transition metals facilitating redox cycling.Decreases antioxidant enzyme activity.

Increases basal cell carcinoma and squamous cell carcinoma risk, but not melanoma risk.

Copper Stimulates metalloproteinase-1 and thus collagen fragmentation.Probable direct effect on oxidative stress within mitochondria.

No associations identified.

UV light Deactivates methionine sulfoxide reductase A and possibly other antioxidant enzymes.Major effect on pyrimidines.

All forms of skin neoplasia.

PHOTOAGING

The major contributing factor to skin aging is ultravio-let radiation (UV light). There are three types of UV light in the spectrum: UV A, B and C; however, only UV A and B have any bearing on skin aging, as UV C is absorbed in the atmosphere, leading to the formation of the ozone layer, and hence does not reach the Earth’s surface. UV B has a wavelength of 280–320 nm and an energy of 3.94–4.43eV, and UV A has a wavelength of 320–400 nm and an energy of 3.10–3.94eV. UV A and UV B are both associated with direct DNA damage due to nucleic acid absorption of wavelengths within these ranges; UV B is absorbed more so in the epidermis and its basal layer, however UV A is able to penetrate further through the skin and hence also has the potential to disturb nucleic acids dermal cells.

In order to gauge the various factors influencing UV light damage to skin, it is important to look at several different layers which the radiation must penetrate prior to its random entry into a cell. First, before the UV radia-tion can even reach the skin it must first reach the Earth’s

FIGURE 2.1 Illustration of how latitude affects the path of UV light from the sun through the ozone layer.

1. OXIDATIVE STRE

atmosphere (Fig. 2.1); given the Earth’s elliptical orbit, this is more likely at perihelion, in January, when the sun is 3.4% closer to the Earth than at aphelion, in July. Hence the Southern hemisphere receives more UV light during their summer than is received in the Northern hemisphere. Photoaging would thus be expected to be greater at a location in the Southern hemisphere which is equidistant from the equator in terms of latitude to a location in the Northern hemisphere. In essence, popula-tions in the Southern hemisphere are at relatively greater risk of skin aging compared with those living in the Northern hemisphere.

Secondly, UV light which reaches the Earth’s atmo-sphere is then subjected to two types of scattering which predominantly affect the amount of radiation reaching the Earth’s surface. One type is Rayleigh scattering: this is isotropic scattering of photons by molecules in the Earth’s atmosphere: N2, O2 and ozone (O3, formed by absorption of UV C photons). The depth of the ozone layer is there-fore, on average, greatest where there is the most UV C radiation. As O3 has a molecular size similar to wave-lengths in the UV B range, UV B radiation is twice as likely to be absorbed than UV A by the ozone layer. Hence, somewhere between ten and a hundred times more UV A reaches the Earth’s surface than UV B depending on the depth of the ozone layer. This depth depends on the angle of incidence of the sun rays (Fig. 2.1), with areas closer to the equator having a shorter distance across the ozone layer for light to traverse. The average thickness of the ozone layer is around 50 km, so that, at the equinox, a location 45° latitude, such as Bordeaux in France, will have a traversal path of 70.2 km, 40% greater.

The other type of scattering is known as Mie’s scatter-ing; this is scattering brought about predominantly by water particles. Water particles are so large in compari-son to the wavelengths of UV radiation that they scatter

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1. OXIDATIVE STRE

very large amounts of light. Large, dense formations of water droplets lead to very little light penetration, and this explains why cloud cover obscures sunlight to such a great extent. Nevertheless, a proportion of pho-tons do get through, though the thicker the cloud cover, the darker it is during the day. This has major impli-cations not only for skin aging, but also for vitamin D production. Another consideration is that the lower the altitude where someone lives, the greater is the chance of Rayleigh’s scattering. Lower altitudes may well have greater cloud cover, and are thus subject to more Mie’s scattering and hence, less exposure to UV radia-tion. Practically, this means that someone working in an observatory in the Atacama desert is at very high risk of photoaging.

Despite the considerable scattering, UV radiation is so abundant that skin is still exposed to a vast number of photons over years, most especially in areas that are not covered by clothing or thick hair. Once the light hits the surface of the skin it may (a) reflect off the skin, (b) be transmitted through into the skin matrix, or (c) both. To determine which course the photons will take, Fresnel’s laws can be used; these laws determine the transmittance and reflection of radiation based upon (i) the refractive indices of the mediums involved (refrac-tive index of air = 1.00 and the refractive index of the epidermis = ∼1.36), (ii) the angle of incidence of the light on the epidermis, and (iii) the polarity of light (either s-polarized or p-polarized, dependent on electric field planes).

Given the non-uniformity of epidermal surfaces, there are a multitude of potential angles of incidence. Calculations are not simple to determine the amount of reflection, but it has been estimated that approximately 5% of photons are reflected from the surface of skin. However, further photons leave the skin due to scat-tering effects, similar to those within the atmosphere, within the skin matrix itself. UV radiation can be scat-tered or absorbed once inside the epidermis, and also the dermis in the case of UV A. The main particles which scatter light are lipids and proteins in the extracellular fluid, keratins and melanins in the epidermis, and colla-gens and elastins in the dermis. Mitochondria also cause scattering in both epidermis and dermis. This scattering is isotropic, hence the photons could move in any direc-tion, even being scattered back out of the skin. Absorp-tion can also occur, the main absorptive particles of UV light being melanin, keratin, nucleic acid and aromatic amino acids. Melanins absorb UV light greatest from a wavelength of ∼300 nm, hence short-wavelength UV B light is scattered by melanin rather than absorbed. Ker-atin mostly absorbs short wavelengths of light, its peak absorption coming at around 280 nm and steadily fall-ing from then on as the wavelength increases, dropping off just above the wavelengths of UV light. Absorption

XIDATIVE STRESS

by these particles prevents absorption by nucleic acid molecules; hence, this is why sunlight exposure leads to either tanning or sunburn, depending on the amount of melanin. UV light-induced increase in melanins lies behind one of the characteristic features of skin aging, an increase in pigmented spots. However large amounts of melanin can also be harmful as melanins scatter short wavelengths of UV B light and this can lead to increased DNA damage. Table 2.5 summarizes the factors that influence the extent of UV radiation reaching skin cells.

Both UV A and UV B damage skin and predispose to neoplasia by direct DNA damage. In addition, UV damage to mitochondrial DNA represents a possible oxidative stress pathway to photoaging of the skin. However UV radiation can also affect oxidative stress directly. An example is the reduction of methionine sulfoxide reductase A activity and content in cul-tured human keratinocytes exposed to UV A radia-tion.31 Methionine sulfoxide reductase levels were also reduced in sun-exposed skin compared to non-sun-exposed skin in 16 female subjects.31 Methionine sulfoxide reductase activity reduction may lead to less oxygen free radical processing because these react with methionine in proteins to form methionine sulfoxide.

TABLE 2.5 Factors that Influence the Extent of Uv Radiation Reaching Skin Cells

Factor Influencing UV Light Reaching Skin Cells Pertinent Parameters

Distance of sun from earth Perihelion occurs in January, so Southern hemisphere at greater relative risk.

Ozone layer Absorbs both UV A and UV B.

Latitude Determines the length of the path through the ozone layer – greater with higher latitudes.

Atmospheric scattering Rayleigh scattering. Shorter wavelengths are scattered more than long ones. Hence high levels of UV scattering and also why the sky appears blue.

Water droplet scattering Mie’s scattering from larger particles in the atmosphere. Explains why thicker clouds appear darker.

Reflection of light from skin Probably only 5% of light is reflected.

Scattering of light from skin surface

Probably larger effect than reflection.

Melanin content of skin Absorbs UV A, but scatters UV B, so may actually worsen effects in epidermis (only UV A reaches the dermis).

REFEREn

Accumulation of oxidized proteins is a feature of the epidermis as it ages,32 and in addition, proteins can be degraded by the cross-linked lipid peroxidation prod-uct, 4-hydroxy-2-nonenol.33 UV light irradiation of the epidermis in a hairless rat model showed decreases in the number of Langerhans’ cells, and this relates to changes in oxidative stress enzymes34 — which may explain, in part, the reduced immune function of the skin that occurs with age.

Along with effects on enzymes that provide antioxi-dant defenses, UV light may well affect other enzyme systems that impact skin aging. One example is 11-beta-hydroxysteroid dehydrogenase, of which the 11-beta-HSD1 isoform that activates cortisol is expressed in human epidermal keratinocytes and dermal fibroblasts rather than the 11-beta-HSD2 isoform that inactivates cortisol. Many features of skin aging, such as dermal thinning, also occur in high glucocorticoid states, both in disease (e.g. Cushing’s disease) and iatrogeni-cally. 11-beta-HSD1 mRNA expression is higher in older adults and higher still in sun-exposed skin.35 This dem-onstrates the uncertainty of the extent of any effect of photoaging being mediated via oxidative stress.

CONCLUSIONS

The skin is a large organ and has some unique features in terms of oxidative stress effects on its aging. First, it receives much of its oxygen directly from the atmosphere rather than from the blood supply; this means that free radical oxygen species can also be derived directly from the atmosphere, as in cigarette smoke, rather than being generated within cells. Second, it is exposed to other atmospheric pollutants, especially ambient particulate matter, to a far greater degree than other organs. Again, these represent an important source of generating free radical oxygen species. Third, the skin, unlike other organs, is exposed to UV light and this, too, may con-tribute to skin aging through oxidative stress pathways.

Skin aging is not monolithic. Increased numbers of pig-mented spots probably relate most strongly to photoag-ing, although NO also promotes melaninogenic changes. Wrinkles and sagging reflect more the loss of collagen and elastin fibres from the dermal matrix, and these processes are influenced by oxidative stress. Wrinkling and sagging, however, both depend on changes to sub-cutaneous tissues that occur with age so that skin aging correlates with age-related changes in other organs. The degree to which oxidative stress contributes to an individual person’s skin aging is difficult to ascertain given the multiple factors that influence skin aging, but skin is easily accessible and does afford an easy oppor-tunity to study oxidative stress in a tissue other than blood.

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CES 21

SUMMARY POINTS

• Skin aging is multidimensional, relating to different pathways.

• Appearances of skin aging relate not only to changes within the skin, but also to changes, especially loss, of underlying subcutaneous tissues.

• Oxidative stress is determined by the balance between free radical oxygen species generation and processing of these species by enzymatic and non-enzymatic antioxidant systems in the skin.

• The most important antioxidant enzymes in the skin are superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase.

• Important environmental exposures that affect skin aging through oxidative stress are cigarette smoking, ambient particulate matter, arsenic, copper and UV light.

• UV B penetrates the epidermis only, whereas UV A penetrates both epidermis and dermis.

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