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Photodermatol Photoimmunol Photomed2000; 16: 239244 CopyrightC Munksgaard 2000

Printed in Denmark All rights reserved

Munksgaard Copenhagen

ISSN 0905-4383

Review article

Photoaging of human skin

M. Berneburg, H. Plettenberg, J. Krutmann

Clinical and Experimental Photodermatology, Dept. of Dermatology, Heinrich-Heine-University, Dusseldorf, Germany

Chronic sun exposure causes photoaging of human

skin, a process that is characterized by clinical, histo-

logical and biochemical changes which differ from

alterations in chronologically aged but sun-protected

skin. Within recent years, substantial progress has

been made in unraveling the underlying mechanisms

of photoaging. Induction of matrix metalloproteinases

as a consequence of activator protein (AP)-1 and nu-clear factor (NF)-kB activation as well as mutations

of 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 such

as heliodermatosis, actinic dermatosis, and accelerated

skin aging. Photoaged, chronically sun-exposed skin has

characteristics in common with sun-protected, chronolo-

gically aged skin. However, there are features which are

found 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 sunlight

or 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-exposure

of the skin to ultraviolet light. Therefore, photoaging will

be of increasing concern in the future.

The clinical and histological characteristics of

photoaged skin have been known for some time (1); how-ever, not until recently have the underlying molecular

mechanisms responsible for the specific macro- and micro-

Abbreviations:

EGF, epidermal growth factor; ERK, extracellular signal-regulated

kinase; 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, tissue

specific inhibitor of matrix metalloproteinases.

239

This has increased our understanding of photoaging

significantly and has led to new prophylactic and

therapeutic strategies aimed at the prevention and re-

pair of the detrimental effects of chronic sun-exposure

on 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 selected

transcription factors (AP-1, NF-kB) in photoaging has

been demonstrated and it has been found that mutations of

mitochondrial DNA may also be involved. The elucidation

of these pathophysiological mechanisms provides the basis

for evaluating the efficacy of photo(aging)protective sub-

stances and might help in the development of new strategies

which will provide protection and repair of photoaged hu-

man skin. Previous reviews on this topic have described the

different aspects of photoaging (2 4). Hence, this review

will only briefly summarize the clinical and histological fea-

tures of photoaged skin and then focus on recent findings

regarding the photobiological and molecular mechanisms

responsible 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 superimposes

these changes. However, changes induced by chronic sun-

exposure can occur well before signs of chronic skin aging.

While there is wide interindividual variation with regards

to clinical features of photoaged skin, depending mostly

on factors such as skin type, nature of sun-exposure (oc-

cupational vs. recreational), hairstyle, dress and possible

individual repair capacity, there are several common

characteristics. These features occur strictly on sun-ex-

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Berneburg et al.

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 and

impaired wound healing (4). Most of these attributes are

caused by dermal changes. The most prominent epidermal

changes are pigmentary alterations such as lentigines and

diffuse 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. The

stratum 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 basal

membrane is increased, possibly reflecting damage to

basal keratinocytes and the distribution of melanocytes

along the basal membrane is irregular and these cells vary

widely in size, dendricity and pigmentation (5, 6).

In the dermis there is a vertical gradient of damage

consistent with progressive attenuation of UV exposure.

Depth and severity of dermal changes depend on the de-

gree of acquired damage. The most prominent histological

feature of photoaging is elastosis (1). Altered elastic fibers

Fig. 1. Photoaging of human skin: UVB light is mostly

absorbed in the epidermis, primarily comprising keratino-

cytes. Transcription factors such as AP-1 and NF-kB are

induced in the epidermis. These factors in turn then in-

duce the expression of MMPs in a yet uncharacterized

fashion. UVA light reaches into the dermis where it is ab-

sorbed by fibroblasts. UVA-induced generation of ROS

leads to the expression of MMPs and induction of muta-

tions of mtDNA.

240

can span a varying portion of the dermal compartment.

Elastosis generally begins at the junction of papillary and

reticular dermis (7) and it is not observed in chronologic-

ally aged skin. Another prominent feature of photoaged

skin is the replacement of mature collagen fibers by colla-

gen with a distinct basophilic appearance. This is called

basophilic degeneration. Further changes characterizing

photoaged skin include a large increase in deposition ofglycosaminoglycans and fragmented elastic fibers, (8, 9)

as well as dermal extracellular matrix proteins such as

elastin (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 its

wavelength, it interacts with different cells that are located

at 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 (UVA

320400 nm) penetrates deeper and can interact with both

epidermal 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 with

darker skin exhibit clinical signs of photoaging at much

later stages than fair-skinned people (1). Induction of skin

pigmentation by oligonucleotides containing thymine di-

nucleotide (pTpT) sequence motifs has been shown to

protect from skin cancer- and photoaging-related features

(18, 19). Induction of skin pigmentation therefore may be

one of the feasible strategies to protect skin from photo-

aging and will be discussed later in this review. Once UV

light has reached the cells of the skin, the different wave-

lengths exert their specific effects. UVA light mostly acts

indirectly through generation of reactive oxygen species

(ROS), which subsequently can exert a multitude of effects

such as lipid peroxidation, activation of transcription fac-

tors and generation of DNA-strand breaks. While UVB

light can also generate ROS, its main mechanism of action

is the direct interaction with DNA via induction of DNA

damage.

Matrix-metalloproteinasesA wealth of evidence exists indicating that the induction

of matrix metalloproteinases (MMP) play a major role in

the 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 also

induces a wide variety of an ever increasing family of

MMPs. These MMPs can be induced by both UVB and

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Photoaging of human skin

UVA light (2224). As indicated by their name, MMPs

show proteolytic activity to degrade matrix proteins. Each

MMP degrades different components of the dermal ma-

trix proteins, for example, MMP-1 cleaves collagen type

I, II, III and MMP-9, also called gelatinase, degrades col-

lagen type IV, V and gelatin. The activity of MMPs is

tightly regulated not only by transcriptional regulation. It

has also been shown that tissue-specific inhibitors ofMMPs (TIMP) exist that specifically inactivate certain

MMPs (4).

Work by Fisher et al. (25, 26) indicated that activation

of transcription factors might be responsible for MMP

induction. Accordingly, UV exposure of human skin not

only leads to the induction of MMPs but, within hours of

UVB 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 that

was one tenth of the dose necessary for skin reddening

(0.1 minimal erythema dose) induced the expression of

AP-1 and NF-kB within minutes and the expression of

MMPs within hours. Subsequent work by the same group

(26) clarified the pathway by which UV exposure leads to

the degradation of matrix proteins in human skin. Low

dose UVB irradiation activated MAP kinase pathways,

involving the upregulation of epidermal growth factor

(EGF) receptors, the GTP-binding regulatory protein

p21Ras, extracellular signal-regulated kinase (ERK), c-jun

amino 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 elegant

work 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 of

trials (for reviews see 2931).

In addition to activation of transcription factors, a sec-

ond pathophysiological pathway leading to photoaging of

human skin has recently been identified. This pathway is

initiated by alterations at the level of mitochondrial DNA.

Mitochondrial DNAMitochondria are cell-organelles whose main function is

to 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 complexes

which generate an electrochemical proton gradient used

in the last step of the process to turn ADP and organo-

phosphate into ATP. This process is not completely error

free and ultimately this leads to the generation of ROS,

making the mitochondrion the site of the highest ROS

241

turnover in the cell. In close proximity to this site lies the

mitochondrions own genetic material, the mtDNA. The

human mtDNA is a 16 559-bp-long, circular and double-

stranded molecule of which four to ten copies exist per

cell. Mitochondria do not contain any repair mechanism

to remove bulky DNA lesions; although they do contain

base excision repair mechanisms and repair mechanisms

against oxidative damage (32), the mutation frequency ofmtDNA is approximately 50-fold higher than nuclear

DNA (33). Mutations of mtDNA have been found to play

a 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 mtDNA

may play a causative role in the normal aging process with

an accumulation of mtDNA mutations accompanied by a

decline of mitochondrial function (34, 35). Recent evi-

dence indicates that mtDNA mutations not only play a

role in the normal aging process but that they may also

be involved in the process of photoaging.

Initial indications for a role of mtDNA in photoaging

has come from several groups which have demonstrated

that chronically sun-exposed skin showing clinical signs

of photoaging has a higher mutation frequency of the

mtDNA than sun-protected skin (3639). These studies

found several large-scale deletions of mtDNA in

photoaged skin. To explain the generation of these large-

scale deletions in mtDNA, a modified slip-replication

mechanism and a central role of ROS have been postu-

lated (3941). Recent work has been able to provide a

possible link for the involvement of ROS in the generation

of 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 human

fibroblasts 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 mutagenesis

is mediated by singlet oxygen. This not only provided a

link between the proposed generation mechanism of large-

scale deletions and ROS but also further supported a

possible role of mtDNA mutations in the process of

photoaging. These in vitro studies have been extended invivo (Plettenberg, Berneburg, Krutmann, unpublished re-

sults) where repetitive irradiation of normal human skin

also led to the induction of the common deletion. In vitro,

the common deletion disappears after the cells are no

longer exposed to UV light, while in vivo, in human skin

the common deletion in human skin could still be detected

up to 4 months after cessation of the irradiation regimen.

An initial indication as to whether these mutations are of

functional relevance for photoaging has recently been

given. Employing the in vitro test system described before,

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Berneburg et al.

Fig. 2. Proposed pathophysiology of mitochondrial muta-

tions: Exposure to UV light induces the generation of

ROS, which in turn generate mutations of mtDNA. These

mutations may (i) serve as a memory for damage inflicted

to cells and (ii) reduce the cells capacity to carry out

OXPHOS. This process may in turn lead to the generation

of more ROS.

it could be demonstrated that there is a close correlation

between the existence of the common deletion and a de-

crease of mitochondrial function as well as expression of

a metalloproteinase that is causally involved in photo-

aging. The appearance of the common deletion was paral-

leled by a reduction in cellular oxygen consumption and

mitochondrial membrane potential (yD), which are

markers for mitochondrial function. Most interestingly,

there was also a close association between the induction

of the metalloproteinase MMP-1 with the occurrence of

the common deletion, while its tissue-specific inhibitor re-

mained unaltered (Berneburg, Plettenberg, Krutmann,

unpublished results). These changes of photoaged skin

may provide a memory-function for previously inflicted

UV damage and the reduction of the OXPHOS, which

may lead to more ROS (Fig. 2). However, more studies

are 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 to

production of singlet oxygen. This indicates that sub-

stances with ROS-quenching potential may be employedto prevent photoaging of human skin. By inhibiting the

translation 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 photoaging

may provide strategies of protection and repair of these

processes. As discussed above, production of melanin in

242

the skin is one of the most effective ways to protect against

the 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 pTpTs

not only induced tanning of the skin but also provided

protective effects against photocarcinogenesis and photo-

aging (19), providing a new and possibly powerful tool to

improve the bodys own sun-protection.A well established way to protect skin against detrimen-

tal effects of sunlight is the application of organic and

inorganic UV filters found in conventional sunscreen

preparations. Newer formulas provide protection against

UVB 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 protective

effect against photocarcinogenesis and photoaging is

widely accepted. However, there is controversy in the

literature with regards to the effects that these substances

have on the immune function of the skin, since protected

skin can then be exposed much longer to sunlight without

getting sunburned.

A new protective strategy has emerged from our under-

standing that oxidative stress plays a major role in the

induction of photoaging. A large number of antioxidants

have been found to exhibit protective effects against the

different ROS involved in photoaging (4346). The data

suggesting these protective effects against ROS-induced

photoaging derives mainly from in vitro studies. Although

the above-mentioned substances are already commercially

available, in order to prove their efficacy, in vivo studies

are needed that provide reproducible data in human skin.

As described earlier, new model systems are emerging that

make these studies feasible and that allow the investiga-

tion of the different pathophysiological endpoints such as

induction of MMP, transcription factors and mitochon-

drial DNA.

Improvement of the bodys endogenous pigmentation

and the application of exogenous sun-protectants are

merely 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 known

transrepressor of the photoaging-involved transcription

factor AP-1, when applied before UVB irradiation sub-

stantially abrogated the induction of AP-1 and MMPs.

This abrogation was achieved in a posttranscriptional

mechanism in which RA antagonized AP-1 activation by

inhibition of c-jun protein induction (26). Subsequent

work by the same group indicated that ultraviolet radi-

ation causes a functional vitamin A deficiency and that

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Photoaging of human skin

this deficiency could be overcome by pretreating the skin

with RA. Thus, this work not only provided a mechan-

istical model for the process of photoaging but also a

rationale for the efficacy of RA in the repair of photoaged

skin.

Another strategy for photoprotection is to repair

existing photodamage. Progress in this area may come

from the field of photocarcinogenesis. Studies employinga liposome-encapsulated repair enzyme called photolyase,

derived from the algae Anacystis nidulans, demonstrated

that when applied to human skin, photolyase reached the

lower levels of the skin and removed DNA damage in the

cells (47). Furthermore, removal of the pre-existing DNA

damage led to physiological effects. Previous studies had

demonstrated that immunosuppression of UV-irradiated

skin is caused by generation of DNA damage in immune

cells of the skin. In a recent study, application of the repair

enzyme photolyase restored the skins immune responsive-

ness; this was shown to be due to the removal of DNA

damage (48). Since photocarcinogenesis and photoaging

have features in common, it is tempting to speculate that

removal 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 and

repair the alterations associated with photoaging of our

skin.

ConclusionsOur understanding of the complex process of photoaging

has increased significantly in recent years. Elucidating the

underlying mechanisms involved in photoaging is of para-

mount importance for the design of specific effective

therapeutic and protective strategies for the improvement

of public health.

References1. Gilchrest BA, Rogers G. Photoaging. In: Lim H, Soter N, eds.

Clinical Photomedicine. New York: Marcel Dekker, 1993: 95

111.

2. Kligman LH. The hairless mouse model for photoaging. Clin

Dermatol 1996: 14: 183195.

3. Miyachi Y. Photoaging from an oxidative standpoint. J Dermatol

Sci 1995: 9: 7986.

4. Scharffetter-Kochanek K. Photoaging of the connective tissue of

skin: its prevention and therapy. Adv Pharmacol 1997: 38: 639

655.

5. Gilchrest BA, Blog FB, Szabo G. Effects of aging and chronic

sun exposure on melanocytes in human skin. J Invest Dermatol

1979: 73: 141143.

6. Breathnach AS, Wylie LM. Electron microscopy of melanocytes

and melanosomes in freckled human epidermis. J Invest Derma-

tol 1964: 42: 389394.

7. Kligman AM. Early destructive effects of sunlight on human

skin. JAMA 1969: 210: 23772380.

8. Mitchell RE. Chronic solar elastosis: A light and electron micro-

scopic study of the dermis. J Invest Dermatol 1967: 48: 203220.

243

9. Chen VL, Fleischmajer R, Schwartz E, Palaia M, Timpl R. Im-

munochemistry of elastotic material in sun-damaged skin. J In-

vest Dermatol 1986: 87: 334337.

10. Smith JG, Davidson EA, Sams WM, Clark RD. Alterations in

human dermal connective tissue with age and chronic sun dam-

age. J Invest Dermatol 1962: 39: 347350.

11. Braverman IM, Fonferko E. Studies in cutaneous aging: I. The

elastic fiber network. J Invest Dermatol 1982: 78: 434443.

12. Uitto J. Connective tissue biochemistry of the aging dermis. Age-

related alterations in collagen and elastin. Dermatol Clin 1986:

4: 433446.13. Bernstein EF, Brown DB, Urbach F et al. Ultraviolet radiation

activates the human elastin promoter in transgenic mice: a novel

in vivo and in vitro model of cutaneous photoaging. J Invest

Dermatol 1995: 105: 269273.

14. Sams WM, Smith JG. The histochemistry of chronically sun-

damaged skin. J Invest Dermatol 1961: 37: 447452.

15. Trautinger F, Trenz A, Raff M, Kokoschka EM. Influence of UV

radiation on dermal collagen content in hairless mice. Arch

Dermatol Res 1989: 281: 144.

16. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th

edn, Philadelphia: Lippincott, 1990: 298300.

17. van der Rest M, Garrone R. Collagen family of proteins. FASEB

J 1991: 5: 28142823.

18. Eller MS, Ostrom K, Gilchrest BA. DNA damage enhances mel-

anogenesis. Proc Natl Acad Sci USA 1996: 6: 10871092.19. Gilchrest BA, Eller MS. DNA photodamage stimulates mel-

anogenesis and other photoprotective responses. J Invest Derma-

tol Symp Proc 1999: 4: 3540.

20. Johnston KJ, Oikarinen AI, Lowe NJ, Clark JG, Uitto J. Ultra-

violet irradiation-induced connective tissue changes in the skin of

hairless mice. J Invest Dermatol 1984: 82: 587590.

21. Oikarinen A. The aging of skin: Chronoaging versus photoaging.

Photodermatol Photoimmunol Photomed 1990: 7: 34.

22. Scharffetter K, Wlaschek M, Hogg A et al. UVA irradiation in-

duces collagenase in human dermal fibroblasts in vitro and in

vivo. Arch Dermatol Res 1991: 283: 506511.

23. Koivukangas V, Kalliloinen M, Autio-Harmainen H, Oikarinen

A. UV-irradiation induces the expression of gelatinases in human

skin in vivo. Acta Derm Venerol 1994: 74: 279282.

24. Fisher GJ, Datta SC, Talwar HS et al. Molecular basis of sun-

induced premature skin ageing and retinoid antagonism. Nature

1996: 379: 335339.

25. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ.

Pathophysiology of premature skin aging induced by ultraviolet

light. N Engl J Med 1997: 337: 14191428.

26. Fisher GJ, Talwar HS, Lin J et al. Retinoic acid inhibits induction

of c-Jun protein by ultraviolet radiation that occurs subsequent

to activation of mitogen-activated protein kinase pathways in hu-

man skin in vivo. J Clin Invest 1998: 101: 14321440.

27. Angel P, Imagawa M, Chiu R et al. Phorbol ester-inducible genes

contain a common cis element recognized by a TPA-modulated

trans-acting factor. Cell 1987: 19: 729739.

28. Sato H, Seiki M. Regulatory mechanism of 92 kDa type IV col-

lagenase gene expression which is associated with invasiveness of

tumor cells. Oncogene 1993: 8: 395405.

29. Kligman AM. Topical retinoic acid (tretinoin) for photoaging:conceptions and misperceptions. Cutis 1996: 57: 142144.

30. Kang S. Photoaging and tretinoin. Dermatol Clin 1998: 16: 357

364.

31. Griffiths CE. Drug treatment of photoaged skin. Drugs Aging

1999: 14: 289301.

32. Yakes FM, Van Houten B. Mitochondrial DNA damage is more

extensive and persists longer than nuclear DNA damage in hu-

man cells following oxidative stress. Proc Natl Acad Sci USA

1997: 94: 514519.

33. Richter C. Oxidative damage to mitochondrial DNA and its re-

lationship to ageing. Int J Biochem Cell Biol 1995: 27: 647653.

34. Wallace DC. Mitochondrial genetics: a paradigm for aging and

degenerative diseases? Science 1992: 256: 628632.

7/28/2019 j.1600-0781.2000.160601.x

6/6

Berneburg et al.

35. Ames BN, Shigenaga MK, Hagen TM. Mitochondrial decay in

aging. Biochim Biophys Acta 1995: 1271: 165170.

36. Yang JH, Lee HC, Lin KJ, Wei YH. A specific 4977-bp deletion

of mitochondrial DNA in human ageing skin. Arch Dermatol

Res 1994: 286: 386390.

37. Yang J-H, Lee H-C, Wei Y-H. Photoageing-associated mitochon-

drial DNA length mutations in human skin. Arch Dermatol Res

1995: 287: 641648.

38. Berneburg M, Gattermann N, Stege H et al. Chronically ultra-

violet-exposed human skin shows a higher mutation frequency

of mitochondrial DNA as compared to unexposed skin and thehematopoietic system. Photochem Photobiol 1997: 66: 271275.

39. Birch-Machin MA, Tindall M, Turner R, Haldane F, Rees JL.

Mitochondrial DNA deletions in human skin reflect photo-

rather than chronologic aging. J Invest Dermatol 1998: 110: 149

152.

40. Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA,

Wallace DC. Spontaneous Kearns-Sayre/chronic external

ophthalmoplegia plus syndrome associated with a mitochondrial

DNA deletion: a slip-replication model and metabolic therapy.

Proc Natl Acad Sci USA 1989: 86: 79527966.

41. Wei YH. Mitochondrial DNA mutations and oxidative damage

in aging and diseases: an emerging paradigm of gerontology and

medicine. Proc Natl Sci Counc Repub China B 1998: 22: 5567.

42. Berneburg M, Grether-Beck S, Krten V et al. Singlet oxygen

mediates the UVA-induced generation of the photoaging-associ-ated mitochondrial common deletion. J Biol Chem 1999: 274:

1534515349.

43. Hoppe U, Bergemann J, Diembeck W et al. Coenzyme Q10, a

cutaneous antioxidant and energizer. Biofactors 1999: 9: 371

378.

44. Poswig A, Wenk J, Brenneisen P et al. Adaptive antioxidant re-

sponse of manganese-superoxide dismutase following repetitive

UVA irradiation. J Invest Dermatol 1999: 112: 1318.

45. Lawrence N. New and emerging treatments for photoaging.

Dermatol Clin 2000: 18: 99112.

244

46. Fuchs J. Potentials and limitations of the natural antioxidants

RRR-alpha-tocopherol, L-ascorbic acid and beta-carotene in cu-

taneous photoprotection. Free Radic Biol Med 1998: 25: 848

873.

47. Yarosh D, Bucana C, Cox P, Alas L, Kibitel J, Kripke M. Localiz-

ation of liposomes containing a DNA repair enzyme in murine

skin. J Invest Dermatol 1994: 103: 461468.

48. Stege H, Roza L, Vink AA et al. Enzyme plus light therapy to

repair immunosuppressive effects on human skin damaged by

ultraviolet B-radiation. Proc Natl Acad Sci USA 2000: 97: 1790

1795.

Acknowledgments

This 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. Krutmann

Clinical and Experimental Photodermatology

Dept. of Dermatology

Heinrich-Heine-University

Moorenstr.5

40225 Dusseldorf

Germany

Tel.: 49 211 811 7627

Fax.: 49 211 811 8830

e-mail: krutmann/rz.uni-duesseldorf.de