Photodermatol Photoimmunol Photomed 2000; 16: 239244 Copyright C Munksgaard 2000Printed in Denmark All rights reservedMunksgaard Copenhagen

ISSN 0905-4383

Review article

Photoaging of human skin

M. Berneburg, H. Plettenberg, J. KrutmannClinical and Experimental Photodermatology, Dept. of Dermatology, Heinrich-Heine-University, Dusseldorf, Germany

Chronic sun exposure causes photoaging of humanskin, a process that is characterized by clinical, histo-logical and biochemical changes which differ fromalterations in chronologically aged but sun-protectedskin. Within recent years, substantial progress hasbeen made in unraveling the underlying mechanismsof photoaging. Induction of matrix metalloproteinasesas a consequence of activator protein (AP)-1 and nu-clear factor (NF)-kB activation as well as mutationsof mitochondrial DNA have been identified recently.

The term photoaging describes distinct clinical, histo-logical and functional features of chronically sun-exposed skin. It has evolved from a variety of terms suchas heliodermatosis, actinic dermatosis, and acceleratedskin aging. Photoaged, chronically sun-exposed skin hascharacteristics in common with sun-protected, chronolo-gically aged skin. However, there are features which arefound exclusively in photoaged skin, making it an inde-pendent entity with its own pathophysiology.

Extended life-span, more spare time and excessive ex-posure to ultraviolet (UV) radiation from natural sunlightor tanning devices, especially in the western population,has resulted in an ever increasing demand to protect hu-man skin against the detrimental effects of UV-exposureof the skin to ultraviolet light. Therefore, photoaging willbe of increasing concern in the future.

The clinical and histological characteristics ofphotoaged skin have been known for some time (1); how-ever, not until recently have the underlying molecularmechanisms responsible for the specific macro- and micro-

Abbreviations:EGF, epidermal growth factor; ERK, extracellular signal-regulatedkinase; GAG, glycosaminoglycans; JNK, c-Jun amino terminal ki-nase; mt, mitochondrial; MAP, mitogen-activated protein; MMP, ma-trix metalloproteinase; MED, minimal erythema dose; NF-kB, Nu-clear factor kB; nm, nanometer; OXPHOS, oxidative phosphoryla-tion; RA, retinoic acid; ROS, reactive oxygen species; TIMP, tissuespecific inhibitor of matrix metalloproteinases.

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This has increased our understanding of photoagingsignificantly and has led to new prophylactic andtherapeutic strategies aimed at the prevention and re-pair of the detrimental effects of chronic sun-exposureon the skin.

Key words: antioxidants; mitochondrial DNA; photo-aging; reactive oxygen species; repetitive sun ex-posure; retinoic acid; sunscreens; ultraviolet light.

scopic alterations been discovered. The role of selectedtranscription factors (AP-1, NF-kB) in photoaging hasbeen demonstrated and it has been found that mutations ofmitochondrial DNA may also be involved. The elucidationof these pathophysiological mechanisms provides the basisfor evaluating the efficacy of photo(aging)protective sub-stances and might help in the development of new strategieswhich will provide protection and repair of photoaged hu-man skin. Previous reviews on this topic have described thedifferent aspects of photoaging (2 4). Hence, this reviewwill only briefly summarize the clinical and histological fea-tures of photoaged skin and then focus on recent findingsregarding the photobiological and molecular mechanismsresponsible for photoaging of human skin.

Clinical featuresNormally aged skin which has not been chronically ex-posed to sunlight is characterized by generalized wrink-ling, dry and thin appearance, and seborrheic keratoses(1). Photoaged skin partly overlaps and superimposesthese changes. However, changes induced by chronic sun-exposure can occur well before signs of chronic skin aging.While there is wide interindividual variation with regardsto clinical features of photoaged skin, depending mostlyon factors such as skin type, nature of sun-exposure (oc-cupational vs. recreational), hairstyle, dress and possibleindividual repair capacity, there are several commoncharacteristics. These features occur strictly on sun-ex-

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posed areas of the body such as the neck, decollete, face,forearms and hands. They comprise leathery appearance,increased wrinkle formation, reduced recoil capacity, in-creased fragility of the skin with blister formation andimpaired wound healing (4). Most of these attributes arecaused by dermal changes. The most prominent epidermalchanges are pigmentary alterations such as lentigines anddiffuse hyperpigmentation (1).

Histological featuresPhotoaged skin has a variable but characteristic histologi-cal appearance, which differs quantitatively and qualitat-ively from sun-protected skin of the same individual. Thestratum corneum of the epidermis may show hyperkera-tosis but is usually normal. The epidermis can be hyper-trophic, atrophic or unaltered. The thickness of the basalmembrane is increased, possibly reflecting damage tobasal keratinocytes and the distribution of melanocytesalong the basal membrane is irregular and these cells varywidely in size, dendricity and pigmentation (5, 6).

In the dermis there is a vertical gradient of damageconsistent with progressive attenuation of UV exposure.Depth and severity of dermal changes depend on the de-gree of acquired damage. The most prominent histologicalfeature of photoaging is elastosis (1). Altered elastic fibers

Fig. 1. Photoaging of human skin: UVB light is mostlyabsorbed in the epidermis, primarily comprising keratino-cytes. Transcription factors such as AP-1 and NF-kB areinduced in the epidermis. These factors in turn then in-duce the expression of MMPs in a yet uncharacterizedfashion. UVA light reaches into the dermis where it is ab-sorbed by fibroblasts. UVA-induced generation of ROSleads to the expression of MMPs and induction of muta-tions of mtDNA.

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can span a varying portion of the dermal compartment.Elastosis generally begins at the junction of papillary andreticular dermis (7) and it is not observed in chronologic-ally aged skin. Another prominent feature of photoagedskin is the replacement of mature collagen fibers by colla-gen with a distinct basophilic appearance. This is calledbasophilic degeneration. Further changes characterizingphotoaged skin include a large increase in deposition ofglycosaminoglycans and fragmented elastic fibers, (8, 9)as well as dermal extracellular matrix proteins such aselastin (1013), glycosaminoglycans (10, 14) and inter-stitial collagen (1517).

PhotobiologyWhich parts of the sunlight cause which feature of photo-aging? UV light penetrates into the skin; depending on itswavelength, it interacts with different cells that are locatedat different depths (Fig. 1). UV light of the shorter wave-lengths (UVB, 280320 nm) is mostly absorbed in the epi-dermis and predominantly affects epidermal cells, i.e.keratinocytes, while longer wavelength UV light (UVA320400 nm) penetrates deeper and can interact with bothepidermal keratinocytes and dermal fibroblasts. Melanin-pigmentation of the skin absorbs UV light and thus pro-tects skin cells from the detrimental effects of UV ex-posure. This provides a rationale of why individuals withdarker skin exhibit clinical signs of photoaging at muchlater stages than fair-skinned people (1). Induction of skinpigmentation by oligonucleotides containing thymine di-nucleotide (pTpT) sequence motifs has been shown toprotect from skin cancer- and photoaging-related features(18, 19). Induction of skin pigmentation therefore may beone of the feasible strategies to protect skin from photo-aging and will be discussed later in this review. Once UVlight has reached the cells of the skin, the different wave-lengths exert their specific effects. UVA light mostly actsindirectly through generation of reactive oxygen species(ROS), which subsequently can exert a multitude of effectssuch as lipid peroxidation, activation of transcription fac-tors and generation of DNA-strand breaks. While UVBlight can also generate ROS, its main mechanism of actionis the direct interaction with DNA via induction of DNAdamage.

Matrix-metalloproteinasesA wealth of evidence exists indicating that the inductionof matrix metalloproteinases (MMP) play a major role inthe pathogenesis of photoaging. While it has been demon-strated that UV light affects the post-translational modi-fication of dermal matrix proteins such as collagen (20,21) it has been known for some years that UV light alsoinduces a wide variety of an ever increasing family ofMMPs. These MMPs can be induced by both UVB and

Photoaging of human skin

UVA light (2224). As indicated by their name, MMPsshow proteolytic activity to degrade matrix proteins. EachMMP degrades different components of the dermal ma-trix proteins, for example, MMP-1 cleaves collagen typeI, II, III and MMP-9, also called gelatinase, degrades col-lagen type IV, V and gelatin. The activity of MMPs istightly regulated not only by transcriptional regulation. Ithas also been shown that tissue-specific inhibitors ofMMPs (TIMP) exist that specifically inactivate certainMMPs (4).

Work by Fisher et al. (25, 26) indicated that activationof transcription factors might be responsible for MMPinduction. Accordingly, UV exposure of human skin notonly leads to the induction of MMPs but, within hours ofUVB exposure, transcription factors AP-1 and NF-kB,which are known stimulatory factors of MMP genes (27,28), are induced. It has been shown at the RNA and pro-tein levels that in human skin, exposure to UVB light thatwas one tenth of the dose necessary for skin reddening(0.1 minimal erythema dose) induced the expression ofAP-1 and NF-kB within minutes and the expression ofMMPs within hours. Subsequent work by the same group(26) clarified the pathway by which UV exposure leads tothe degradation of matrix proteins in human skin. Lowdose UVB irradiation activated MAP kinase pathways,involving the upregulation of epidermal growth factor(EGF) receptors, the GTP-binding regulatory proteinp21Ras, extracellular signal-regulated kinase (ERK), c-junamino terminal kinase (JNK) and p38. Elevated c-jun to-gether with constitutively expressed c-fos increased acti-vation of transcription factor AP-1. Thus, this elegantwork not only unraveled the complex mechanistic path-ways underlying the process of photoaging but also pro-vided a rationale for the efficacy of retinoic acid (RA)which has previously been demonstrated in a multitude oftrials (for reviews see 2931).

In addition to activation of transcription factors, a sec-ond pathophysiological pathway leading to photoaging ofhuman skin has recently been identified. This pathway isinitiated by alterations at the level of mitochondrial DNA.

Mitochondrial DNAMitochondria are cell-organelles whose main function isto generate energy for the cell. This is achieved by a multi-step process called oxidative phosphorylation (OXPHOS)or electron-transport-chain. Located at the inner mito-chondrial membrane are five multi-protein complexeswhich generate an electrochemical proton gradient usedin the last step of the process to turn ADP and organo-phosphate into ATP. This process is not completely errorfree and ultimately this leads to the generation of ROS,making the mitochondrion the site of the highest ROS

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turnover in the cell. In close proximity to this site lies themitochondrions own genetic material, the mtDNA. Thehuman mtDNA is a 16 559-bp-long, circular and double-stranded molecule of which four to ten copies exist percell. Mitochondria do not contain any repair mechanismto remove bulky DNA lesions; although they do containbase excision repair mechanisms and repair mechanismsagainst oxidative damage (32), the mutation frequency ofmtDNA is approximately 50-fold higher than nuclearDNA (33). Mutations of mtDNA have been found to playa causative role in degenerative diseases such as Alzhei-mers disease, chronic progressive external ophthalmople-gia and Kearns-Sayre syndrome. In addition to degenerat-ive diseases, it has been found that mutations of mtDNAmay play a causative role in the normal aging process withan accumulation of mtDNA mutations accompanied by adecline of mitochondrial function (34, 35). Recent evi-dence indicates that mtDNA mutations not only play arole in the normal aging process but that they may alsobe involved in the process of photoaging.

Initial indications for a role of mtDNA in photoaginghas come from several groups which have demonstratedthat chronically sun-exposed skin showing clinical signsof photoaging has a higher mutation frequency of themtDNA than sun-protected skin (3639). These studiesfound several large-scale deletions of mtDNA inphotoaged skin. To explain the generation of these large-scale deletions in mtDNA, a modified slip-replicationmechanism and a central role of ROS have been postu-lated (3941). Recent work has been able to provide apossible link for the involvement of ROS in the generationof the most frequent mtDNA deletion, the so-called com-mon deletion (42). Employing an in vitro model system,it has been possible to demonstrate that normal humanfibroblasts when repetitively exposed for 3 weeks to suble-thal doses of UVA light exhibit a time- and dose-depend-ent increase of the common deletion. In the same study,it was shown that this UVA-induced mtDNA mutagenesisis mediated by singlet oxygen. This not only provided alink between the proposed generation mechanism of large-scale deletions and ROS but also further supported apossible role of mtDNA mutations in the process ofphotoaging. These in vitro studies have been extended invivo (Plettenberg, Berneburg, Krutmann, unpublished re-sults) where repetitive irradiation of normal human skinalso led to the induction of the common deletion. In vitro,the common deletion disappears after the cells are nolonger exposed to UV light, while in vivo, in human skinthe common deletion in human skin could still be detectedup to 4 months after cessation of the irradiation regimen.An initial indication as to whether these mutations are offunctional relevance for photoaging has recently beengiven. Employing the in vitro test system described before,

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Fig. 2. Proposed pathophysiology of mitochondrial muta-tions: Exposure to UV light induces the generation ofROS, which in turn generate mutations of mtDNA. Thesemutations may (i) serve as a memory for damage inflictedto cells and (ii) reduce the cells capacity to carry outOXPHOS. This process may in turn lead to the generationof more ROS.

it could be demonstrated that there is a close correlationbetween the existence of the common deletion and a de-crease of mitochondrial function as well as expression ofa metalloproteinase that is causally involved in photo-aging. The appearance of the common deletion was paral-leled by a reduction in cellular oxygen consumption andmitochondrial membrane potential (yD), which aremarkers for mitochondrial function. Most interestingly,there was also a close association between the inductionof the metalloproteinase MMP-1 with the occurrence ofthe common deletion, while its tissue-specific inhibitor re-mained unaltered (Berneburg, Plettenberg, Krutmann,unpublished results). These changes of photoaged skinmay provide a memory-function for previously inflictedUV damage and the reduction of the OXPHOS, whichmay lead to more ROS (Fig. 2). However, more studiesare needed to strengthen the link between mtDNA muta-tions and the process of photoaging.

Assessment of the underlying photobiological mechan-isms has revealed that, similar to UVA-induced MMP-in-duction, the generation of mtDNA mutations is due toproduction of singlet oxygen. This indicates that sub-stances with ROS-quenching potential may be employedto prevent photoaging of human skin. By inhibiting thetranslation of transiently damaging ROS effects into gen-etically imprinted mutations, quenchers may not only pro-tect from short-term damage of UV but also prevent long-term effects of UV exposure.

PhotoprotectionUnderstanding the underlying mechanisms of photoagingmay provide strategies of protection and repair of theseprocesses. As discussed above, production of melanin in

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the skin is one of the most effective ways to protect againstthe sun. Work by Eller & Gilchrest indicated that oligo-nucleotides that contain thymine dinucleotides (pTpT) in-duce tanning of the skin (18). The presence of these pTpTsnot only induced tanning of the skin but also providedprotective effects against photocarcinogenesis and photo-aging (19), providing a new and possibly powerful tool toimprove the bodys own sun-protection.

A well established way to protect skin against detrimen-tal effects of sunlight is the application of organic andinorganic UV filters found in conventional sunscreenpreparations. Newer formulas provide protection againstUVB and UVA light and some even against infrared radi-ation. The efficacy of these substances has been demon-strated in a wide variety of studies and their protectiveeffect against photocarcinogenesis and photoaging iswidely accepted. However, there is controversy in theliterature with regards to the effects that these substanceshave on the immune function of the skin, since protectedskin can then be exposed much longer to sunlight withoutgetting sunburned.

A new protective strategy has emerged from our under-standing that oxidative stress plays a major role in theinduction of photoaging. A large number of antioxidantshave been found to exhibit protective effects against thedifferent ROS involved in photoaging (4346). The datasuggesting these protective effects against ROS-inducedphotoaging derives mainly from in vitro studies. Althoughthe above-mentioned substances are already commerciallyavailable, in order to prove their efficacy, in vivo studiesare needed that provide reproducible data in human skin.As described earlier, new model systems are emerging thatmake these studies feasible and that allow the investiga-tion of the different pathophysiological endpoints such asinduction of MMP, transcription factors and mitochon-drial DNA.

Improvement of the bodys endogenous pigmentationand the application of exogenous sun-protectants aremerely prophylactic tactics. Improving the repair of al-ready existing damage would complete a strategy to de-crease detrimental effects of sun exposure.

A large body of data exists demonstrating that a de-rivative of vitamin A, all-trans retinoic acid, exibits suchproperties. In vitro and in vivo studies have recently dem-onstrated that all-trans retinoic acid, which is a knowntransrepressor of the photoaging-involved transcriptionfactor AP-1, when applied before UVB irradiation sub-stantially abrogated the induction of AP-1 and MMPs.This abrogation was achieved in a posttranscriptionalmechanism in which RA antagonized AP-1 activation byinhibition of c-jun protein induction (26). Subsequentwork by the same group indicated that ultraviolet radi-ation causes a functional vitamin A deficiency and that

Photoaging of human skin

this deficiency could be overcome by pretreating the skinwith RA. Thus, this work not only provided a mechan-istical model for the process of photoaging but also arationale for the efficacy of RA in the repair of photoagedskin.

Another strategy for photoprotection is to repairexisting photodamage. Progress in this area may comefrom the field of photocarcinogenesis. Studies employinga liposome-encapsulated repair enzyme called photolyase,derived from the algae Anacystis nidulans, demonstratedthat when applied to human skin, photolyase reached thelower levels of the skin and removed DNA damage in thecells (47). Furthermore, removal of the pre-existing DNAdamage led to physiological effects. Previous studies haddemonstrated that immunosuppression of UV-irradiatedskin is caused by generation of DNA damage in immunecells of the skin. In a recent study, application of the repairenzyme photolyase restored the skins immune responsive-ness; this was shown to be due to the removal of DNAdamage (48). Since photocarcinogenesis and photoaginghave features in common, it is tempting to speculate thatremoval of DNA damage in skin cells may not only pro-tect against skin cancer but also prevent photoaging.

Overall, within recent years several promising strat-egies have emerged that may allow us, in spite of in-creasing sun exposure of the population, to protect andrepair the alterations associated with photoaging of ourskin.

ConclusionsOur understanding of the complex process of photoaginghas increased significantly in recent years. Elucidating theunderlying mechanisms involved in photoaging is of para-mount importance for the design of specific effectivetherapeutic and protective strategies for the improvementof public health.

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AcknowledgmentsThis work has been supported in part by the BMBF (07-UVB C5/7) and the European Commission (QRCT-1999-01590).

Accepted for publication May 17, 2000

Corresponding author:J. KrutmannClinical and Experimental PhotodermatologyDept. of DermatologyHeinrich-Heine-UniversityMoorenstr.540225 DusseldorfGermanyTel.: pi49 211 811 7627Fax.: pi49 211 811 8830e-mail: krutmann/rz.uni-duesseldorf.de