Advertisement

Molecular aspects of skin ageing

  • Elizabeth C. Naylor
    Affiliations
    Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M13 9PT, UK

    School of Translational Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, M13 9PT UK
    Search for articles by this author
  • Rachel E.B. Watson
    Affiliations
    Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M13 9PT, UK

    School of Translational Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, M13 9PT UK
    Search for articles by this author
  • Michael J. Sherratt
    Correspondence
    Corresponding author at: School of Biomedicine, Faculty of Medical and Human Sciences, The University of Manchester, 1st floor Stopford Building, Oxford Road, Manchester, M13 9PT, UK. Tel.: +44 161 275 1439; fax: +44 161 275 5171.
    Affiliations
    Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M13 9PT, UK

    School of Biomedicine, The University of Manchester, Manchester, M13 9PT UK
    Search for articles by this author

      Abstract

      Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin.
      The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFβ). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation.

      Keywords

      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'

      Subscribe:

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

      References

        • Yaar M.
        • Gilchrest B.A.
        Photoageing: mechanism, prevention and therapy.
        Br J Dermatol. 2007; 157: 874-887
        • Langton A.K.
        • Sherratt M.J.
        • Griffiths C.E.M.
        • Watson R.E.B.
        Review article: a new wrinkle on old skin: the role of elastic fibres in skin ageing.
        Int J Cosmet Sci. 2010; 32: 330-339
        • Montagna W.
        • Kirchner S.
        • Carlisle K.
        Histology of sun-damaged human-skin.
        J Am Acad Dermatol. 1989; 21: 907-918
        • Warren R.
        • Gartstein V.
        • Kligman A.M.
        • Montagna W.
        • Allendorf R.A.
        • Ridder G.M.
        Age, sunlight, and facial skin: a histologic and quantitative study.
        J Am Acad Dermatol. 1991; 25: 751-760
        • Agache P.G.
        • Monneur C.
        • Leveque J.L.
        • Derigal J.
        Mechanical-properties and youngs modulus of human-skin in vivo.
        Arch Dermatol Res. 1980; 269: 221-232
        • Shapiro S.D.
        • Endicott S.K.
        • Province M.A.
        • Pierce J.A.
        • Campbell E.J.
        Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of d-aspartate and nuclear weapons-related radiocarbon.
        J Clin Invest. 1991; 87: 1828-1834
        • Ritz-Timme S.
        • Laumeier I.
        • Collins M.J.
        Aspartic acid racemization: evidence for marked longevity of elastin in human skin.
        Br J Dermatol. 2003; 149: 951-959
        • Jennissen H.P.
        Ubiquitin and the enigma of intracellular protein-degradation.
        Eur J Biochem. 1995; 231: 1-30
        • Bailey A.J.
        Molecular mechanisms of ageing in connective tissues.
        Mech Ageing Dev. 2001; 122: 735-755
        • Robert L.
        • Robert A.M.
        • Fulop T.
        Rapid increase in human life expectancy: will it soon be limited by the aging of elastin?.
        Biogerontology. 2008; 9: 119-133
        • Gosline J.
        • Lillie M.
        • Carrington E.
        • Guerette P.
        • Ortlepp C.
        • Savage K.
        Elastic proteins: biological roles and mechanical properties.
        Philos Trans: Biol Sci. 2002; 357: 121-132
        • Heim A.J.
        • Matthews W.G.
        • Koob T.J.
        Determination of the elastic modulus of native collagen fibrils via radial indentation.
        Appl Phys Lett. 2006; 89: 3
        • El-Domyati M.
        • Attia S.
        • Saleh F.
        • et al.
        Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin.
        Exp Dermatol. 2002; 11: 398-405
        • Clark J.I.
        Fourier and power law analysis of structural complexity in cornea and lens.
        Micron. 2001; 32: 239-249
        • Graham H.K.
        • Hodson N.W.
        • Hoyland J.A.
        • et al.
        Tissue section AFM: in situ ultrastructural imaging of native biomolecules.
        Matrix Biol. 2010; 29: 254-260
        • Keene D.R.
        • Sakai L.Y.
        • Lunstrum G.P.
        • Morris N.P.
        • Burgeson R.E.
        Type-VII collagen forms an extended network of anchoring fibrils.
        J Cell Biol. 1987; 104: 611-621
        • Christiano A.M.
        • Anhalt G.
        • Gibbons S.
        • Bauer E.A.
        • Uitto J.
        Premature termiantion codons in the type-VII collagen gene (COL7A1) underlie severe, mutilating recessive dystrophic epidermolysis-bullosa.
        Genomics. 1994; 21: 160-168
        • Fleischmajer R.
        • Utani A.
        • MacDonald E.D.
        • et al.
        Initiation of skin basement membrane formation at the epidermo-dermal interface involves assembly of laminins through binding to cell membrane receptors.
        J Cell Sci. 1998; 111: 1929-1940
        • Baldock C.
        • Sherratt M.J.
        • Shuttleworth C.A.
        • Kielty C.M.
        The supramolecular organization of collagen VI microfibrils.
        J Mol Biol. 2003; 330: 297-307
        • Scacheri P.C.
        • Gillanders E.M.
        • Subramony S.H.
        • et al.
        Novel mutations in collagen VI genes - Expansion of the Bethlem myopathy phenotype.
        Neurology. 2002; 58: 593-602
        • Vanegas O.C.
        • Bertini E.
        • Zhang R.Z.
        • et al.
        Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.
        Proc Natl Acad Sci U S A. 2001; 98: 7516-7521
        • Doubal S.
        • Klemera P.
        Visco-elastic response of human skin and aging.
        J Am Aging Assoc. 2002; 25: 115-117
        • Diridollou S.
        • Berson M.
        • Vabre V.
        • et al.
        An in vivo method for measuring the mechanical properties of the skin using ultrasound.
        Ultrasound Med Biol. 1998; 24: 215-224
        • Akhtar R
        • Sherratt MJ
        • Cruickshank JK
        • Derby B.
        Characterizing the elastic properties of tissues.
        Mater Today. 2011; 14: 96-105
        • Aaron B.B.
        • Gosline J.M.
        Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers.
        Biopolymers. 1981; 20: 1247-1260
        • Kielty C.M.
        • Sherratt M.J.
        • Shuttleworth C.A.
        Elastic fibres.
        J Cell Sci. 2002; 115: 2817-2828
        • Sherratt M.J.
        Tissue elasticity and the ageing elastic fibre.
        Age. 2009; 31: 305-325
        • Ramirez F.
        • Carta L.
        • Lee-Arteaga S.
        • Liu C.
        • Nistala H.
        • Smaldone S.
        Fibrillin-rich microfibrils – structural and instructive determinants of mammalian development and physiology.
        Connect Tissue Res. 2008; 49: 1-6
        • Cotta-Periera G.
        • Guerro Rodriguez F.
        • Bittencourt-Sampaio S.
        Oxytalan, elaunin and elastic firbes in human skin.
        J Invest Dermatol. 1978; 66: 143-148
        • Dahlback K.
        • Ljungquist A.
        • Lofberg H.
        • Dahlback B.
        • Engvall E.
        • Sakai L.Y.
        Fibrillin immunoreactive fibers constitute a unique network in the human dermis: Immunohistochemical comparison of the distributions of fibrillin, vitronectin, amyloid P component, and orcein stainable structures in normal skin and elastosis.
        J Invest Dermatol. 1990; 94: 284-291
        • Rock M.J.
        • Cain S.A.
        • Freeman L.J.
        • et al.
        Molecular basis of elastic fiber formation – critical interactions and a tropoelastin-fibrillin-1 cross-link.
        J Biol Chem. 2004; 279: 23748-23758
        • Notbohm H.
        • Nokelainen M.
        • Myllyharju J.
        • Fietzek P.P.
        • Muller P.K.
        • Kivirikko K.I.
        Recombinant human type II collagens with low and high levels of hydroxylysine and its glycosylated forms show marked differences in fibrillogenesis in vitro.
        J Biol Chem. 1999; 274: 8988-8992
        • Danielson K.G.
        • Baribault H.
        • Holmes D.F.
        • Graham H.
        • Kadler K.E.
        • Iozzo R.V.
        Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility.
        J Cell Biol. 1997; 136: 729-743
        • Graham H.K.
        • Holmes D.F.
        • Watson R.B.
        • Kadler K.E.
        Identification of collagen fibril fusion during vertebrate tendon morphogenesis. The process relies on unipolar fibrils and is regulated by collagen–proteoglycan interaction.
        J Mol Biol. 2000; 295: 891-902
        • Waller J.M.
        • Maibach H.I.
        Age and skin structure and function, a quantitative approach (II): protein, glycosaminoglycan, water, and lipid content and structure.
        Skin Res Technol. 2006; 12: 145-154
        • Warren R.
        • Gartstein V.
        • Kligman A.M.
        • Montagna W.
        • Allendorf R.A.
        • Ridder G.M.
        Age, sunlight, and facial skin – a histologic and quantitative study.
        J Am Acad Dermatol. 1991; 25: 751-760
        • Escoffier C.
        • de Rigal J.
        • Rochefort A.
        • Vasselet R.
        • Leveque J.L.
        • Agache P.G.
        Age-related mechanical properties of human skin: an in vivo study.
        J Invest Dermatol. 1989; 93: 353-357
        • Gilchrest B.A.
        A review of skin ageing and its medical therapy.
        Br J Dermatol. 1996; 135: 867-875
        • Robert C.
        • Lesty C.
        • Robert A.M.
        Aging of the skin – study of elastic fiber network modifications by computerized image-analysis.
        Gerontology. 1988; 34: 291-296
        • Ghersetich I.
        • Lotti T.
        • Campanile G.
        • Grappone C.
        • Dini G.
        Hyaluronic-acid in cutaneous intrinsic aging.
        Int J Dermatol. 1994; 33: 119-122
        • Timar F.
        • Soos G.
        • Szende B.
        • Horvath A.
        Interdigitation index – a parameter for differentiating between young and older skin specimens.
        Skin Res Technol. 2000; 6: 17-20
        • Talwar H.S.
        • Griffiths C.E.M.
        • Fisher G.J.
        • Hamilton T.A.
        • Voorhees J.J.
        Reduced type-I and type-III procollagens in photodamaged adult human skin.
        J Invest Dermatol. 1995; 105: 285-290
        • Craven N.M.
        • Watson R.E.B.
        • Jones C.J.P.
        • Shuttleworth C.A.
        • Kielty C.M.
        • Griffiths C.E.M.
        Clinical features of photodamaged human skin are associated with a reduction in collagen VII.
        Br J Dermatol. 1997; 137: 344-350
        • Bernstein E.F.
        • Underhill C.B.
        • Hahn P.J.
        • Brown D.B.
        • Uitto J.
        Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans.
        Br J Dermatol. 1996; 135: 255-262
        • Watson R.E.B.
        • Griffiths C.E.M.
        • Craven N.M.
        • Shuttleworth C.A.
        • Kielty C.M.
        Fibrillin-rich microfibrils are reduced in photoaged skin. Distribution at the dermal–epidermal junction.
        J Invest Dermatol. 1999; 112: 782-787
        • Kadoya K.
        • Sasaki T.
        • Kostka G.
        • et al.
        Fibulin-5 deposition in human skin: decrease with ageing and ultraviolet B exposure and increase in solar elastosis.
        Br J Dermatol. 2005; 153: 607-612
        • Mitchell R.E.
        Chronic solar dermatosis – a light and electron microscopic study of dermis.
        J Invest Dermatol. 1967; 48: 203
        • Bernstein E.F.
        • Chen Y.Q.
        • Tamai K.
        • et al.
        Enhanced elastin and fibrillin gene-expression in chronically photodamaged skin.
        J Invest Dermatol. 1994; 103: 182-186
        • Karonen T.
        • Jeskanen L.
        • KeskiOja J.
        Transforming growth factor beta 1 and its latent form binding protein-1 associate with elastic fibres in human dermis: accumulation in actinic damage and absence in anetoderma.
        Br J Dermatol. 1997; 137: 51-58
        • Hunzelmann N.
        • Nischt R.
        • Brenneisen P.
        • Eickert A.
        • Krieg T.
        Increased deposition of fibulin-2 in solar elastosis and its colocalization with elastic fibres.
        Br J Dermatol. 2001; 145: 217-222
        • Verzijl N.
        • DeGroot J.
        • Thorpe S.R.
        • et al.
        Effect of collagen turnover on the accumulation of advanced glycation end products.
        J Biol Chem. 2000; 275: 39027-39031
        • Davis E.C.
        Stability of elastin in the developing mouse aorta: a quantitative radioautographic study.
        Histochemistry. 1993; 100: 17-26
        • Rucker R.B.
        • Tinker D.
        Structure and metabolism of arterial elastin.
        Int Rev Exp Pathol. 1977; 17: 1-47
        • Zhang M.C.
        • Pierce R.A.
        • Wachi H.
        • Mecham R.P.
        • Parks W.C.
        An open reading frame element mediates posttranscriptional regulation of tropoelastin and responsiveness to transforming growth factor beta 1.
        Mol Cell Biol. 1999; 19: 7314-7326
        • Stamatas G.N.
        • Estanislao R.B.
        • Suero M.
        • et al.
        Facial skin fluorescence as a marker of the skin's response to chronic environmental insults and its dependence on age.
        Br J Dermatol. 2006; 154: 125-132
        • Konova E.
        • Baydanoff S.
        • Atanasova M.
        • Velkova A.
        Age-related changes in the glycation of human aortic elastin.
        Exp Gerontol. 2004; 39: 249-254
        • Elliott R.J.
        • McGrath L.T.
        Calcification of the human thoracic aorta during aging.
        Calcif Tissue Int. 1994; 54: 268-273
        • Bestetti-bosisio M.
        • Cotelli F.
        • Schiaffino E.
        • Sorgato G.
        • Schmid C.
        Lung calcification in long-term dialyzed patients – a light and electronmicroscopic study.
        Histopathology. 1984; 8: 69-79
        • Jacotot B.
        • Beaumont J.L.
        • Monnier G.
        • Szigeti M.
        • Robert L.
        • Robert B.
        Role of elastic tissue in cholesterol depostion in arterial-wall.
        Nutr Metabol. 1973; 15: 46-58
        • Ritz-Timme S.
        • Collins M.J.
        Racemization of aspartic acid in human proteins.
        Ageing Res Rev. 2002; 1: 43-59
        • Bruel A.
        • Oxlund H.
        Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation endproducts of the rat aorta in relation to age.
        Arteriosclerosis. 1996; 127: 155-165
        • Lai-Fook S.J.
        • Hyatt R.E.
        Effects of age on elastic moduli of human lungs.
        J Appl Physiol. 2000; 89: 163-168
        • Smalls L.K.
        • Wickett R.R.
        • Visscher M.O.
        Effect of dermal thickness, tissue composition, and body site on skin biomechanical properties.
        Skin Res Technol. 2006; 12: 43-49
        • Fisher G.J.
        • Datta S.C.
        • Talwar H.S.
        • et al.
        Molecular basis of sun-induced premature skin ageing and retinoid antagonism.
        Nature. 1996; 379: 335-339
        • Saarialho-Kere U.
        • Kerkela E.
        • Jeskanen L.
        • et al.
        Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage.
        J Invest Dermatol. 1999; 113: 664-672
        • Ashworth J.L.
        • Murphy G.
        • Rock M.J.
        • et al.
        Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.
        Biochem J. 1999; 340: 171-181
        • Chakraborti S.
        • Mandal M.
        • Das S.
        • Mandal A.
        • Chakraborti T.
        Regulation of matrix metalloproteinases: an overview.
        Mol Cell Biochem. 2003; 253: 269-285
        • Sherratt M.J.
        • Bayley C.P.
        • Reilly S.M.
        • Gibbs N.K.
        • Griffiths C.E.M.
        • Watson R.E.B.
        Low-dose ultraviolet radiation selectively degrades chromophore-rich extracellular matrix components.
        J Pathol. 2010; 222: 32-40
        • Cooper D.R.
        • Davidson R.J.
        Effect of ultraviolet irradiation on soluble collagen.
        Biochem J. 1965; 97: 139-147
        • Menter J.M.
        • Cornelison L.M.
        • Cannick L.
        • et al.
        Effect of UV on the susceptibility of acid-soluble Skh-1 hairless mouse collagen to collagenase.
        Photodermatol Photoimmunol Photomed. 2003; 19: 28-34
        • Du H.
        • Fuh R.C.A.
        • Li J.Z.
        • Corkan L.A.
        • Lindsey J.S.
        PhotochemCAD: a computer-aided design and research tool in photochemistry.
        Photochem Photobiol. 1998; 68: 141-142
        • Kim H.H.
        • Lee M.J.
        • Lee S.R.
        • et al.
        Augmentation of UV-induced skin wrinkling by infrared irradiation in hairless mice.
        Mech Ageing Dev. 2005; 126: 1170-1177
        • Lee J.Y.
        • Kim Y.K.
        • Seo J.Y.
        • et al.
        Loss of elastic fibers causes skin wrinkles in sun-damaged human skin.
        J Dermatol Sci. 2008; 50: 99-107
        • Adair-Kirk T.L.
        • Senior R.M.
        Fragments of extracellular matrix as mediators of inflammation.
        Int J Biochem Cell Biol. 2008; 40: 1101-1110
        • Debret R.
        • Antonicelli F.
        • Theill A.
        • et al.
        Elastin-derived peptides induce a T-Helper type 1 polarization of human blood lymphocytes.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1353-1358
        • Peterszegi G.
        • Texier S.
        • Robert L.
        Cell death by overload of the elastin–laminin receptor on human activated lymphocytes: protection by lactose and melibiose.
        Eur J Clin Invest. 1999; 29: 166-172
        • Peterszegi G.
        • Mandet C.
        • Texier S.
        • Robert L.
        • Bruneval P.
        Lymphocytes in human atherosclerotic plaque exhibit the elastin-laminin receptor: potential role in atherogenesis.
        Arteriosclerosis. 1997; 135: 103-107
        • Baranek T.
        • Debret R.
        • Antonicelli F.
        • et al.
        Elastin receptor (Spliced galactosidase) occupancy by elastin peptides counteracts proinflammatory cytokine expression in lipopolysaccharide-stimulated NF-kappa B down-regulation.
        J Immunol. 2007; 179: 6184-6192
        • Guo G.
        • Booms P.
        • Halushka M.
        • et al.
        Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment.
        Circulation. 2006; 114: 1855-1862
        • Houghton A.M.
        • Quintero P.A.
        • Perkins D.L.
        • et al.
        Elastin fragments drive disease progression in a murine model of emphysema.
        J Clin Invest. 2006; 116: 753-759
        • Fahem A.
        • Robinet A.
        • Cauchard J.H.
        • et al.
        Elastokine-mediated up-regulation of MT1-MMP is triggered by nitric oxide in endothelial cells.
        Int J Biochem Cell Biol. 2008; 40: 1581-1596
        • Ntayi C.
        • Labrousse A.L.
        • Debret R.
        • et al.
        Elastin-derived peptides upregulate matrix metalloproteinase-2-mediated melanoma cell invasion through elastin-binding protein.
        J Invest Dermatol. 2004; 122: 256-265
        • Booms P.
        • Pregla R.
        • Ney A.
        • et al.
        RGD-containing fibrillin-1 fragments upregulate matrix metalloproteinase expression in cell culture: a potential factor in the pathogenesis of the Marfan syndrome.
        Hum Genet. 2005; 116: 51-61
        • Isogai Z.
        • Ono R.N.
        • Ushiro S.
        • et al.
        Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein.
        J Biol Chem. 2003; 278: 2750-2757
        • Neptune E.R.
        • Frischmeyer P.A.
        • Arking D.E.
        • et al.
        Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.
        Nat Genet. 2003; 33: 407-411
        • Habashi J.P.
        • Judge D.P.
        • Holm T.M.
        • et al.
        Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.
        Science. 2006; 312: 117-121
        • Kielty C.M.
        • Raghunath M.
        • Siracusa L.D.
        • et al.
        The Tight skin mouse: Demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils.
        J Cell Biol. 1998; 140: 1159-1166
        • ter Heide H.
        • Stumpel C.
        • Pals G.
        • Delhaas T.
        Neonatal Marfan syndrome: clinical report and review of the literature.
        Clin Dysmorphol. 2005; 14: 81-84
        • Sherratt M.J.
        • Bastrilles J.Y.
        • Bowden J.J.
        • Watson R.E.B.
        • Griffiths C.E.M.
        Age-related deterioration in the mechanical function of human dermal fibrillin microfibrils.
        Br J Dermatol. 2006; 155: 240-241
        • Weiss J.S.
        • Ellis C.N.
        • Headington J.T.
        • Tincoff T.
        • Hamilton T.A.
        • Voorhees J.J.
        Topical tretinoin improves photoaged skin - a double-blind vehicle-controlled study.
        J Am Med Assoc. 1988; 259: 527-532
        • Kafi R.
        • Kwak H.S.R.
        • Schumacher W.E.
        • et al.
        Improvement of naturally aged skin with vitamin A (retinol).
        Arch Dermatol. 2007; 143: 606-612
        • Kligman A.M.
        • Leyden J.J.
        Treatment of photoaged skin with topical tretinoin.
        Skin Pharmacol. 1993; 6: 78-82
        • Griffiths C.E.M.
        • Russman A.N.
        • Majmudar G.
        • Singer R.S.
        • Hamilton T.A.
        • Voorhees J.J.
        Restoratrion of collagen formation in photodamaged human skin by tretinoin (retinoic acid).
        N Engl J Med. 1993; 329: 530-535
        • Fisher G.J.
        • Esmann J.
        • Griffiths C.E.M.
        • et al.
        Cellular, immunological and biochemcial-characterization of topical retinoic acid-treated human skin.
        J Invest Dermatol. 1991; 96: 699-707
        • 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.
        J Am Med Assoc. 1990; 263: 3057-3059
        • Watson R.E.B.
        • Craven N.M.
        • Kang S.W.
        • Jones C.J.P.
        • Kielty C.M.
        • Griffiths C.E.M.
        A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents.
        J Invest Dermatol. 2001; 116: 672-678
        • Farwick M.
        • Watson R.E.B.
        • Rawlings A.V.
        • et al.
        Salicyloyl-phytosphingosine: A novel agent for the repair of photoaged skin.
        Int J Cosmet Sci. 2007; 29: 319-329
        • Watson R.E.B.
        • Ogden S.
        • Cotterell L.F.
        • et al.
        A cosmetic ‘anti-ageing’ product improves photoaged skin: a double-blind, randomized controlled trial.
        Br J Dermatol. 2009; 161: 419-426
        • Sivan S.S.
        • Tsitron E.
        • Wachtel E.
        • et al.
        Aggrecan turnover in human intervertebral disc as determined by the racemization of aspartic acid.
        J Biol Chem. 2006; 281: 13009-13014
        • Verzijl N.
        • DeGroot J.
        • Oldehinkel E.
        • et al.
        Age-related accumulation of Maillard reaction products in human articular cartilage collagen.
        Biochem J. 2000; 350: 381-387