Pathogenesis, prevention, and treatment
      The term photoaging refers to premature skin aging caused by repeated exposure to solar ultraviolet (UV) radiation. The photoaged phenotype is characterized by fine and coarse wrinkles, mottled pigmentation, sallow color, and rough textures on habitually sun-exposed skin.
      • Kligman A.M.
      Early destructive effects of sunlight on human skin.
      Histologic and ultrastructural studies have revealed that the major alterations in photoaged skin are localized in the dermal connective tissue. Collagen fibrils, which constitute the bulk of skin connective tissue, become disorganized
      • Bernstein E.F.
      • et al.
      Long-term sun exposure alters the collagen of the papillary dermis: Comparison of sun-protected and photoaged skin by Northern analysis, immunohistochemical staining, and confocal laser scanning microscopy.
      and abnormal amorphous, elastin-containing material
      • Lavker R.M.
      Cutaneous aging: Chronologic versus photoaging.
      accumulates in the dermis, a condition known as solar elastosis. Recent advances in photobiology have provided substantial insight into the process by which UV irradiation causes disarrangement of dermal extracellular matrix. Elucidation of the photoaging mechanisms also has allowed for the identification of therapeutic targets and strategies to prevent photoaging. This article summarizes key findings that represent our current understanding of photoaging, in particular wrinkle formation. The state of our knowledge indicates that topical tretinoin can not only be used to treat photoaging after it has occurred, but is also likely to retard or prevent photoaging as and before it happens. Although this publication is clinical overall, the nature of the subject matter discussed in this article necessitates the inclusion of some basic materials. Whenever possible, the scientific concepts are presented in a nontechnical way.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Clinics in Geriatric Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Angel P.
        • Karin M.
        The role of Jun, Fos and AP-1 complex in cell proliferation and transformation.
        Biochem Biophys Acta. 1991; 1072: 129-157
        • Angel P.
        • Karin M.
        Specific members of the Jun protein family regulate collagenase expression in response to various extracellular stimuli.
        Matrix Suppl. 1992; 1: 156-164
        • Ato H.
        • Seiki M.
        Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells.
        Oncogene. 1993; 8: 395-405
        • Bernstein E.F.
        • et al.
        Long-term sun exposure alters the collagen of the papillary dermis: Comparison of sun-protected and photoaged skin by Northern analysis, immunohistochemical staining, and confocal laser scanning microscopy.
        J Am Acad Dermatol. 1996; 34: 209-218
        • Bhawan J.
        • Gonzalez-Serva A.
        • Nehal K.
        • et al.
        Effects of tretinoin on photodamaged skin: A histologic study.
        Arch Dermatol. 1991; 127: 666-672
        • Bhawan J.
        • Palko M.J.
        • Lee J.
        • et al.
        Reversible histologic effects of tretinoin on photodamaged skin.
        J Geriatr Dermatol. 1995; 3: 62-67
        • Birkedal-Hansen H.
        • Moore W.G.I.
        • Bodden M.K.
        • et al.
        Matrix metalloproteinases: A review.
        Crit Rev Oral Biol Med. 1993; 4: 197-250
        • Chen J.Y.
        • Penco S.
        • Ostrowski J.
        • et al.
        RAR-specific agonist/antagonists which dissociate transactivation and AP-1 transrepression inhibit anchorage-independent cell proliferation.
        EMBO J 1995;. 1995; 14: 1187-1197
      1. Fisher GJ, Choi HC, Bata-Csorgo Z, et al. Ultraviolet irradiation increases matrix metalloproteinase-8 protein in human skin in vivo. J Invest Dermatol, in press

        • Chung K.
        • Agarwal A.
        • Uitto J.
        • et al.
        An AP-1 binding sequence is essential for regulation of the human α2(I) collagen (COL1A2) promoter activity by transforming growth factor-β.
        J Biol Chem. 1996; 271: 3272-3278
        • Deak S.B.M.
        • Pope F.M.
        • Prockop D.J.
        The molecular defect in a nonlethal variant of osteogenesis imperfecta.
        J Biol Chem. 1983; 258: 15192-15197
        • Duell E.A.
        • Kang S.
        • Voorhees J.J.
        Endogenous antioxidant enzyme activities in human skin are decreased by four but not one exposure to ultraviolet light [abstract].
        J Invest Dermatol. 1999; 112: 657
        • Edward D.R.
        • Murphy G.
        • Reynolds J.J.
        • et al.
        Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor.
        EMBO J. 1987; 6: 1899-1904
        • Ellis C.N.
        • Weiss J.S.
        • Hamilton T.A.
        • et al.
        Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin.
        J Am Acad Dermatol. 1990; 23: 629-637
        • Fisher G.J.
        • Voorhees J.J.
        Molecular mechanisms of photoaging and its prevention by retinoic acid: Ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo.
        J Invest Dermatol. 1998; 3: 61-68
        • Fisher G.J.
        • et al.
        Pathophysiology of premature skin aging induced by ultraviolet light.
        N Engl J Med. 1997; 337: 1419-1428
        • Fisher G.J.
        • et al.
        Retinoic acid inhibits induction of c-Jun protein by ultraviolet irradiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo.
        J Clin Invest. 1998; 101: 1432-1440
        • Fisher G.J.
        • Datta S.
        • Wang Z.Q.
        • et al.
        C-Jun-dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoic acid.
        J Clin Invest. 2000; 106: 663-670
        • Fisher G.J.
        • Datta S.C.
        • Talwar H.S.
        • et al.
        Molecular basis of sun-induced premature skin ageing and retinoid antogonism.
        Nature. 1996; 379: 335-339
        • Fisher G.J.
        • Tavakkol A.
        • Griffiths C.E.
        • et al.
        Differential modulation of transforming growth factor-beta 1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin.
        J Invest Dermatol. 1992; 98: 102-108
        • Griffiths C.E.M.
        • Russman A.N.
        • Majmudar G.
        • et al.
        Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid).
        N Engl J Med. 1993; 329: 530-535
      2. Gross J. An essay on biological degradation of collagen In Hay ED (ed): Cell Biology Extracellular Matrix. New York 1981, pp 217–258.

        • Halila R.
        • Peltonen L.
        Purification of human procollagen type III N-proteinase from placenta and preparation of antiserum.
        Biochem J. 1986; 239: 47-52
        • Hasty K.A.
        • Jeffrey J.J.
        • Hibbs M.S.
        • et al.
        The collagen substrate specificity of human neutrophil collagenase.
        J Biol Chem. 1987; 262: 10048-10052
        • Haukipuro K.
        • Meikko J.
        • Risteli L.
        • et al.
        Synthesis of type I collagen in healing wounds in humans.
        Ann Surg. 1991; 213: 75-80
        • Hawk J.L.M.
        • Murphy G.M.
        • Holden C.A.
        The presence of neutrophils in human cutaneous ultraviolet-B inflammation.
        Br J Dermatol. 1988; 118: 27-30
        • Herrlich P.
        • Ponta H.
        Mutual cross-modulation of steroid/retinoic acid receptor and AP-1 transcription factor activities: A novel property with practical implications.
        Trends Endocrinol Metab. 1994; 5: 341-346
        • Herrlich P.
        • Sachsenmaier C.
        • Radler-Pohl A.
        • et al.
        The mammalian UV response: Mechanism of DNA damage induced gene expression.
        Adv Enzyme Regul. 1994; 34: 381-395
        • Hirose T.
        • Patterson C.
        • Pourmotabbed T.
        • et al.
        Structure-function relationship of human neutophil collagenase: Identification of regions responsible for substrate specificity and general proteinase activity.
        Proc Natl Acad Sci. 1993; 90: 2569-2573
        • Hojima Y.
        • McKenzie J.A.
        • Van der Rest M.
        • et al.
        Type I procollagen N proteinase from chick embryo tendons: Purification of a new 500-kDa form of the enzyme and identification of the catalytically active polypeptides.
        J Biol Chem. 1989; 264: 11336-11345
        • Ihn H.
        • LeRoy E.C.
        • Trojanowska M.
        Oncostatin M stimulates transcription of the human α2(I) collagen gene via the Sp1/Sp3-binding site.
        J Biol Chem. 1997; 272: 24666-24672
        • Inagaki Y.
        • Truter S.
        • Tanaka S.
        • et al.
        Overlapping pathways mediate the opposing actions of tumor necrosis factor-α and transforming growth factor-β on α2(I) collagen gene transcription.
        J Biol Chem. 1995; 270: 3353-3358
        • Jimenez S.A.
        • et al.
        Functional analysis of human α1(I) procollagen gene promoter.
        J Biol Chem. 1994; 269: 12684-12691
        • Kahari V.M.
        • Saarialho-Kere U.
        Matrix metalloproteinase in skin [review].
        Exp Dermatol. 1997; 6: 199-213
        • Kang S.
        • Fisher G.
        • Duell E.
        • et al.
        The antioxidant n-acetyl cysteine increases the content of the endogenous antioxidant glutathione and prevents UV-induction of matrix metalloproteinases in human skin in vivo [abstract].
        J Invest Dermatol. 1999; 112: 658
        • Kligman A.M.
        Early destructive effects of sunlight on human skin.
        JAMA. 1969; 10: 2377-2380
        • Knauper V.
        • Docherty A.J.P.
        • Smith B.
        • et al.
        Analysis of the contribution of the hinge region of human neutrophil collagenase (HNC, MMP-8) to stability and collagenolytic activity by alanine scanning mutagenesis.
        FEBS Lett. 1997; 405: 60-64
        • Lavker R.M.
        Cutaneous aging: Chronologic versus photoaging.
        in: Gilchrest B.A. Photoaging. Blackwell Science, Cambridge, MA1995: 123-135
        • Liu X.
        • et al.
        A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling.
        J Cell Biol. 1995; 130: 227-237
        • Lo Y.
        • Cruz T.
        Involvement of reactive oxygen species in cytokine and growth factor induction of c-Fos expressions in chondrocytes.
        J Biol Chem. 1995; 270: 11727-11730
        • Massague J.
        TGF-β signal transduction.
        Annu Rev Biochem. 1998; 67: 753-791
        • Matrisian L.M.
        • Hogan B.L.
        Growth factor-regulated proteases and extracellular matrix remodeling during mammalian devlopment.
        Curr Top Dev Biol. 1990; 24: 219-259
        • Oikarinen A.
        • Autio P.
        • Kiistala U.
        • et al.
        A new method to measure type I and III collagen synthesis in human skin in vivo: Demonstration of decreased collagen synthesis after topical glucocorticoid treatment.
        J Invest Dermatol. 1992; 98: 220-225
        • Olsen B.R.
        New insights into the function of collagens from genetic analysis.
        Curr Opin Cell Biol. 1995; 7: 720-727
        • Pfahl M.
        Nuclear receptor/AP-1 interaction.
        Endocr Rev. 1993; 14: 651-658
        • Philips N.
        • Bashey R.I.
        • Jimenez S.A.
        Increased α1(I) procollagen gene expression in tight skin (TSK) mice myocardial fibroblasts is due to a reduced interaction of a negative regulatory sequence with AP-1 transcription factor.
        J Biol Chem. 1995; 270: 9313-9321
        • Quinones S.
        • Buttice G.
        • Kurkinen M.
        Promoter elements in the transcriptional activation of the human stromelysin-1 gene by the inflammatory cytokine, interleukin.
        Biochem J. 1994; 302: 471-477
        • Risteli J.
        • Elomaa I.
        • Niemi S.
        • et al.
        Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: A new serum marker of bone collagen degradation.
        Clin Chem. 1993; 39: 635-640
        • Rossert J.A.
        • Garrett L.A.
        Regulation of type I collagen synthesis.
        Kidney Int. 1995; 47: 1421-1432
        • Saatcioglu F.
        • Claret F.X.
        • Karin M.
        Negative transcriptional regulation by nuclear receptors.
        Semin Cancer Biol. 1994; 5: 347-359
        • Shingleton W.D.
        • Hodges D.J.
        • Brick P.
        • et al.
        Collagenase: A key enzyme in collagen turnover.
        Biochem Cell Biol. 1996; 74: 759-775
        • Smith L.T.
        • Holbrook K.A.
        • Madri J.A.
        Collagen types I, III and V in human embryonic and fetal skin.
        Am J Anat. 1986; 175: 507-521
        • Talwar H.S.
        • Griffiths C.E.M.
        • Fisher G.J.
        • et al.
        Reduced type I and type III procollagens in photodamaged adult human skin.
        J Invest Dermatol. 1995; 105: 285-290
        • Tavakkol A.
        • Zouboulis C.C.
        • Duell E.A.
        • et al.
        A retinoic acid-inducible skin-specific gene (RIS-1/psoriasin): Molecular cloning and analysis of gene expression in human skin in vivo and cultured skin cells in vitro.
        Mol Biol Rep. 1994; 20: 75-83
        • Uitto J.
        Collagen polymorphism: Isolation and partial characterization of alpha 1(I)-trimer molecules in normal human skin.
        Arch Biochem Biophys. 1979; 192: 371-379
        • Varga J.
        • Rosenbloom J.
        • Jimenez S.
        Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts.
        Biochem J. 1987; 247: 597-604
        • Verrecchia F.
        • Pessah M.
        • Atfi A.
        • et al.
        Tumor necrosis factor-alpha inhibits transforming growth factor-beta/Smad signaling in human dermal fibroblasts via AP-1 activation.
        J Biol Chem. 2000; 275: 30226-30231
        • Wang Z.Q.
        • Talwar H.S.
        • Kang S.
        • et al.
        Glucocorticoid and retinoic acid inhibit ultraviolet irradiation induction of cytokine and matrix-degrading metalloproteinase genes through distinct mechanisms in human skin in vivo [abstract].
        J Invest Dermatol. 1999; 112: 490
        • Weiss J.S.
        • Ellis C.N.
        • Headington J.T.
        • et al.
        Topical tretinoin improves photoaged skin: A double-blind vehicle-controlled study.
        JAMA. 1988; 259: 527-532
      3. Wenstrup RJ, Murad S, Pinnell SR. Collagen In Goldsmith LA (ed): Physiology, Biochemistry, and Molecular Biology of the Skin, ed 2. Oxford, 1991, pp 481–508.

        • Whisler R.
        • Goyette M.
        • Grants I.
        • et al.
        Sublethal levels of oxidant stress stimulate multiple serine/threonine kinases and suppress protein phosphatases in Jurkat T cells.
        Arch Biochem Biophys. 1995; 319: 23-35
        • Woessner Jr, J.F.
        Matrix metalloproteinases and their inhibitors in connective tissue remodeling.
        FASEB J. 1991; 5: 2145-2154
        • Woodley D.
        • Yamauchi M.
        • Wynn K.
        • et al.
        Collagen telopeptides (cross-linking sites) play a role in collagen gel lattice contraction.
        J Invest Dermatol. 1991; 97: 580-585
        • Woodley D.T.
        • Zelickson A.S.
        • Briggaman R.A.
        • et al.
        Treatment of photoaged skin with topical tretinoin increases epidermal-dermal anchoring fibrils: A preliminary report.
        JAMA. 1990; 263: 3057-3059