Clinual atid l'.xp(-n?ni-nlal dermatology 19*>1; !(>: .il.S 323.
Review Article
Aspects of cutaneous ageing K ATT lAR INF. L.DALZTET., Department of Dermatology, ihuvei'sily Hospital, Qut'ens Medical Centre, Nottingham NG7 2UH, UK Accepted for publication 21 March 1991
Summary 'Ageing i.s a multistep, multifaceted, time-dependent phenomenon charaeterized by the decreased ability of a system to respond to exogenous and endogenous stress from either phj.sical, chemical or biologic agents'.' CAUaneous ageing provides a visible model ot the interaction between endogenous (intrinsic) factors and exogenous (extrinsic) factors. Tn skin, the principal extrinsicfactor is ultra\ iolet light (UV) which is responsible for the eonsrellation ol' changes termed photoagcing. Tn recent years, much interest has been directed towards defining the ageing processes in skin and excellent comprehensive reviews have been compiled.^'"' This review aims to highlight several areas of developing knowledge, and focuses on the potential importance of environmental changes as they influence skin ageing and carcinogenesis. Repeated reference to the effects of U\' on the skin are inevitable in any review of skin ageing and this is scarcely surprising as the skin contains many cellH as well as subcellular and extracellular chromophores which are capable of absorbing energy within the UV' spectrum."^ Cxiluiar chromophores include among others keratinoevtes, melanoeytcs, f.angerhans cells, dermal fibroblasts and mast cells. Subcellular chromophores include keratin, melanin, collagen, elastin and a number of proteins, lipids and steroids (such as vitamin T^). Urocanic acid, a photoisomerization product ofthe amino-acid histidine, may provide some limited phoroprotection and some believe it lo be important in UV induced immunosuppression.'' Understanding events at the molecular and biochemical level has unfortunately not been paralleled by clinical ad\ anccs and the common, troublesome skin-problems of old age such as eaneer., xerosis and pruritus remain a major cause of morbidity and yet are poorly explained.
budget, and pharmaceutical conip-iiiit-'^^ 'ire now said ro spend almost 50",, of their budgets on ageing-.'* The cultured skin-fibroblast has provided a very useful model for the study of cellular senescence. 'I'he pioneering work of Hayflick and iMoorhead' first showed thai the rcplicative life of human skin fibroblasts was finite. Ha\ flick went on to show that the proliferative eapacity of embryonic cells as measured by population doublings w as greater than in fihrobiasls from adult subjects.** This observation has been confirmed many rimes since and an inverse correlation exists between the proliferative capacity of cells and donor age.'' The search to define the
although the question as to whether such eells provide an accurate model of cellular seneseence ;// vivo is still eontroversial. The theories ofeellular senescence in human eulturedfibroblasts and the evidence supporting- them ha\-e recently been reviewed hy Goldstein.'" Tt appears likely rhat cellular seneseence resembles terminal diflerenriation with arrest ofthe cell at the G]/S stage of the eel] cyde. F-vidcnce that an inhibitor\ protein is synthesized in senescent cells is supported by the work of Lumpkin et al.'^ who have shown that micro-injection of polyadenylated DNA from senescent cells int C et al. Study of skin ageing as a 41. Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUV.A) and ultrafunction of social and professional conditions: mndilications violet B radiation. New England Journal of Medicine 1991); of the rhcological parameters measured wilh a non-invasive 322: 1093 1097. method-indentometry. Gerontology 1988:34:284 290. 23. Uillo J, Fazio MJ, Olsen 1">R. Cutaneous aging: molecular 42. Tanaka K, Miura N, Salokata I et al. Analysis of a human
References
CUTANEOUS ACilTNG
43.
44. 45.
46. 47. 4S.
49. 50.
51. 52.
53. 54. 55. 56. 57.
58. 59. 60. 61. 62.
DNA excision repair gene involved in group A xeroderma pigmcntosuni and containing a /inc-lingcr domain. Nalurc 1990: 348: 73 76. " Liu S-C, Meagher K. Hanawall PC. Role of solar conditioning m DNA repair response a nil survival of human epidermal kcralmocytcs following UV irradiation. JournalojTnvestigatire Dermatology I98.S; 85: 93 97. ' Lehman AR. Bridges BA. Sunlight-induced cancer: some new aspects and implications ofthe xeroderma pigmenlosum model. BrilLsh Journal of Dermatology 1990; 122: 115- I 19. Norris PCi, Limb GA. Hamblin AS el al. Immune funciion. niulani Irequencv and cancer risk in the DNA repair defective gcnodcrinaioscs teroderma pigmentosum. Cockayne's syndrome and trichothiiKlystrophy. Journal of Investigative Dermatology \99{y 94: 94 100. ' Boyle J, Mackie RM. Briggs JD ct al. Cancers, warls and sunshine in renal transplant patients: a case control study. Lancei 1984: I: 702 705. Kripkc M l , l''ishcr MS. immunologic aspects of tumor induction b> ultraviolet radiation. National Caneer Institute Monographs 1978; 50: 179 183, Hcrscy P. Haran G. Hasic Eel al. Alteration of T ceil subsets and induction of suppressor T cell activity in normal subjects after exposure to sunlight. Journal of Immunology 1983; 131: 171 174. '" Theirs iii 1, Mai/e JC, Spicer SS cl al. The elfecl of aging and chronic sun exposure on human Langerhans cell populations. Journal of fmesliga/ive Dermatology 1984; 82: 223-226. Fisher MS. Menter JM. Willis'l. Uhraviolct radiationinduced suppression of conlaci hypersensitivity in relation to padimalc () and oxyben/one. Journal of Tnvestigalive Dermatotogy 1989; 92: 337 341. Young AR, Senescence and sunscreens. British Journal of Dermatology 1990. 122: 1 I I 114. Ross JA. HowicSEM, Norval M etal. Ultra-violet-irradiated urocanic acid suppresses delaycd-type hypersensitivity to herpes simplex virus in mice. Journal of Inrestit^ativc Dermatology 1986:87:630 633. ' Lloyd Roberts D. Incidence of non-melanoma skin cancer m West (ilamorgan. Soulh Wales. British Journal off)ermalology 1990; 122: 399 403, Rogers CiS. Ciilchrest BA, Fnvironmcnlal influences on skin ageing. British Journal of Dermatology 1990; 122: IsuppI 35) 55 60. Cjlass ACJ. Hoover KN. The emergingepidemic of melanoma and squamous cell skin cancer. Journal of ifie America?! Mcdieal As.sociaiion 1989:262:2097 2100. McDonagh AJ(i, Wright AL. Cotton DWK, Bkehan SS. Malignant melanoma in Sheffield 1971 -88. British Journal of Dermatology l'J9(); 12.'?(Suppl. 37): 37 38 (.Abstract). Nil! consensus development conference: sunlight, ultraviolet radiation and ihc skin: program and abstracts. May 8 10 1989, Belhesda. Md. Washington. D.C:. Department of Health and fluman Services: 65 66. Russell Jones R. O/one depletion and cancer risk. Lancet 1987: 2:443 446. Atkinson R.I. Maltliews WA, Newman PA ct al. Evidence ol' the mid-la liUidc impact of Antarctic o/oue depletion. NadAre 1989; 340: 29i) 294. Lindiey D. ns. Dermatologic Clinics 1986: 4: 371 377. 66. Kligman AM, Ciraham JA. The psychology of appearance in the elderly, Dermalologic Clinies 1986:4:^()| 507, 67 "/•/;(' Holy Bible (King James). Psalms xc Vs.9. 68. Kligman LH, Akin FJ. Kligman AM. Prevention of iillraviolet damage to the dermis o\' hairless mice by sunscrtvns. J o u r n a l of I n v e s t i g a t i v e D e r m a t o l o g y i 9 S 2 : 7 8 : I K I i 8 9 .
69. Kligman LH. Akin EJ, Kligman .AM. Sunscreens promote repair of ultraviolet radialion-induced dermal tianiasjc. Journal of Investigative Dermatology 1983; 81: ')8-IO2. 70. Kligman LH, Akin I'M. Kligman AM. Sunscreens prevent ultraviolet photocarcinogenesis. Journal of the American Academy of Dermatology 1980; 3: 30 35, 71. Matsuoka LY, Worisman J. Hanifan N et al. Chrome sunscreen use decreases circulating conccnlraliiins oC 25hydroxy vitamin D. Archives of Dermatologv I98K; 124: IN02 1804. 72. Prystowsky JH. Photoprotcciion and ihc vitamin i) status of Ihe elderly. Archives of Dermaiology 1988: 124: 1844 I.S48. 73, Kligman 1,H. Effects of a]i-//(//i.v-reunoic acsd on the dermis of hairless mice. Journal of the Ameriean Aeademv of Dermatology 1986; 15:779 7K5. 74. Bauer EA, Sell/.er JL. F.isen A / , Retinoic acid inhibition of collagenasc and gclalinase expression in human fibroblasi cultures: evidence for a duLii mechanism. Journal of Inresngative fyermatology \9^y.»\:\(:A 169. 75, Woodley DT, Zelicksi>n .'\S, Briggaman R.A et al. Trcalincnl of pholoaged skin with topical tretinoin increases epidermaldermal anchoring librils. Journal of ihc American Medical Assoeiation 1990:263:3057 3059. 76. Kligman LH. Chen HD. Kligman AM. I'oiiical rctinoic acid enhances the repair of ultraviolet damaged connective tissue. Connective Tissue Rescareh 1984: 12: 13') 150. 77. Kligman .AM, GroveCiL. Hirose K etal. Tcipical trciiixiin for p h o t o a g e d s k i n . Journal
78. 79. 80.
81. 82, 83.
of the American
Academy
i)f
Derma-
tology 1986; 15: 836 S59.' Weiss JS. Ellis CN. Headingt
Review Article
Aspects of cutaneous ageing K ATT lAR INF. L.DALZTET., Department of Dermatology, ihuvei'sily Hospital, Qut'ens Medical Centre, Nottingham NG7 2UH, UK Accepted for publication 21 March 1991
Summary 'Ageing i.s a multistep, multifaceted, time-dependent phenomenon charaeterized by the decreased ability of a system to respond to exogenous and endogenous stress from either phj.sical, chemical or biologic agents'.' CAUaneous ageing provides a visible model ot the interaction between endogenous (intrinsic) factors and exogenous (extrinsic) factors. Tn skin, the principal extrinsicfactor is ultra\ iolet light (UV) which is responsible for the eonsrellation ol' changes termed photoagcing. Tn recent years, much interest has been directed towards defining the ageing processes in skin and excellent comprehensive reviews have been compiled.^'"' This review aims to highlight several areas of developing knowledge, and focuses on the potential importance of environmental changes as they influence skin ageing and carcinogenesis. Repeated reference to the effects of U\' on the skin are inevitable in any review of skin ageing and this is scarcely surprising as the skin contains many cellH as well as subcellular and extracellular chromophores which are capable of absorbing energy within the UV' spectrum."^ Cxiluiar chromophores include among others keratinoevtes, melanoeytcs, f.angerhans cells, dermal fibroblasts and mast cells. Subcellular chromophores include keratin, melanin, collagen, elastin and a number of proteins, lipids and steroids (such as vitamin T^). Urocanic acid, a photoisomerization product ofthe amino-acid histidine, may provide some limited phoroprotection and some believe it lo be important in UV induced immunosuppression.'' Understanding events at the molecular and biochemical level has unfortunately not been paralleled by clinical ad\ anccs and the common, troublesome skin-problems of old age such as eaneer., xerosis and pruritus remain a major cause of morbidity and yet are poorly explained.
budget, and pharmaceutical conip-iiiit-'^^ 'ire now said ro spend almost 50",, of their budgets on ageing-.'* The cultured skin-fibroblast has provided a very useful model for the study of cellular senescence. 'I'he pioneering work of Hayflick and iMoorhead' first showed thai the rcplicative life of human skin fibroblasts was finite. Ha\ flick went on to show that the proliferative eapacity of embryonic cells as measured by population doublings w as greater than in fihrobiasls from adult subjects.** This observation has been confirmed many rimes since and an inverse correlation exists between the proliferative capacity of cells and donor age.'' The search to define the
although the question as to whether such eells provide an accurate model of cellular seneseence ;// vivo is still eontroversial. The theories ofeellular senescence in human eulturedfibroblasts and the evidence supporting- them ha\-e recently been reviewed hy Goldstein.'" Tt appears likely rhat cellular seneseence resembles terminal diflerenriation with arrest ofthe cell at the G]/S stage of the eel] cyde. F-vidcnce that an inhibitor\ protein is synthesized in senescent cells is supported by the work of Lumpkin et al.'^ who have shown that micro-injection of polyadenylated DNA from senescent cells int C et al. Study of skin ageing as a 41. Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUV.A) and ultrafunction of social and professional conditions: mndilications violet B radiation. New England Journal of Medicine 1991); of the rhcological parameters measured wilh a non-invasive 322: 1093 1097. method-indentometry. Gerontology 1988:34:284 290. 23. Uillo J, Fazio MJ, Olsen 1">R. Cutaneous aging: molecular 42. Tanaka K, Miura N, Salokata I et al. Analysis of a human
References
CUTANEOUS ACilTNG
43.
44. 45.
46. 47. 4S.
49. 50.
51. 52.
53. 54. 55. 56. 57.
58. 59. 60. 61. 62.
DNA excision repair gene involved in group A xeroderma pigmcntosuni and containing a /inc-lingcr domain. Nalurc 1990: 348: 73 76. " Liu S-C, Meagher K. Hanawall PC. Role of solar conditioning m DNA repair response a nil survival of human epidermal kcralmocytcs following UV irradiation. JournalojTnvestigatire Dermatology I98.S; 85: 93 97. ' Lehman AR. Bridges BA. Sunlight-induced cancer: some new aspects and implications ofthe xeroderma pigmenlosum model. BrilLsh Journal of Dermatology 1990; 122: 115- I 19. Norris PCi, Limb GA. Hamblin AS el al. Immune funciion. niulani Irequencv and cancer risk in the DNA repair defective gcnodcrinaioscs teroderma pigmentosum. Cockayne's syndrome and trichothiiKlystrophy. Journal of Investigative Dermatology \99{y 94: 94 100. ' Boyle J, Mackie RM. Briggs JD ct al. Cancers, warls and sunshine in renal transplant patients: a case control study. Lancei 1984: I: 702 705. Kripkc M l , l''ishcr MS. immunologic aspects of tumor induction b> ultraviolet radiation. National Caneer Institute Monographs 1978; 50: 179 183, Hcrscy P. Haran G. Hasic Eel al. Alteration of T ceil subsets and induction of suppressor T cell activity in normal subjects after exposure to sunlight. Journal of Immunology 1983; 131: 171 174. '" Theirs iii 1, Mai/e JC, Spicer SS cl al. The elfecl of aging and chronic sun exposure on human Langerhans cell populations. Journal of fmesliga/ive Dermatology 1984; 82: 223-226. Fisher MS. Menter JM. Willis'l. Uhraviolct radiationinduced suppression of conlaci hypersensitivity in relation to padimalc () and oxyben/one. Journal of Tnvestigalive Dermatotogy 1989; 92: 337 341. Young AR, Senescence and sunscreens. British Journal of Dermatology 1990. 122: 1 I I 114. Ross JA. HowicSEM, Norval M etal. Ultra-violet-irradiated urocanic acid suppresses delaycd-type hypersensitivity to herpes simplex virus in mice. Journal of Inrestit^ativc Dermatology 1986:87:630 633. ' Lloyd Roberts D. Incidence of non-melanoma skin cancer m West (ilamorgan. Soulh Wales. British Journal off)ermalology 1990; 122: 399 403, Rogers CiS. Ciilchrest BA, Fnvironmcnlal influences on skin ageing. British Journal of Dermatology 1990; 122: IsuppI 35) 55 60. Cjlass ACJ. Hoover KN. The emergingepidemic of melanoma and squamous cell skin cancer. Journal of ifie America?! Mcdieal As.sociaiion 1989:262:2097 2100. McDonagh AJ(i, Wright AL. Cotton DWK, Bkehan SS. Malignant melanoma in Sheffield 1971 -88. British Journal of Dermatology l'J9(); 12.'?(Suppl. 37): 37 38 (.Abstract). Nil! consensus development conference: sunlight, ultraviolet radiation and ihc skin: program and abstracts. May 8 10 1989, Belhesda. Md. Washington. D.C:. Department of Health and fluman Services: 65 66. Russell Jones R. O/one depletion and cancer risk. Lancet 1987: 2:443 446. Atkinson R.I. Maltliews WA, Newman PA ct al. Evidence ol' the mid-la liUidc impact of Antarctic o/oue depletion. NadAre 1989; 340: 29i) 294. Lindiey D. ns. Dermatologic Clinics 1986: 4: 371 377. 66. Kligman AM, Ciraham JA. The psychology of appearance in the elderly, Dermalologic Clinies 1986:4:^()| 507, 67 "/•/;(' Holy Bible (King James). Psalms xc Vs.9. 68. Kligman LH, Akin FJ. Kligman AM. Prevention of iillraviolet damage to the dermis o\' hairless mice by sunscrtvns. J o u r n a l of I n v e s t i g a t i v e D e r m a t o l o g y i 9 S 2 : 7 8 : I K I i 8 9 .
69. Kligman LH. Akin EJ, Kligman .AM. Sunscreens promote repair of ultraviolet radialion-induced dermal tianiasjc. Journal of Investigative Dermatology 1983; 81: ')8-IO2. 70. Kligman LH, Akin I'M. Kligman AM. Sunscreens prevent ultraviolet photocarcinogenesis. Journal of the American Academy of Dermatology 1980; 3: 30 35, 71. Matsuoka LY, Worisman J. Hanifan N et al. Chrome sunscreen use decreases circulating conccnlraliiins oC 25hydroxy vitamin D. Archives of Dermatologv I98K; 124: IN02 1804. 72. Prystowsky JH. Photoprotcciion and ihc vitamin i) status of Ihe elderly. Archives of Dermaiology 1988: 124: 1844 I.S48. 73, Kligman 1,H. Effects of a]i-//(//i.v-reunoic acsd on the dermis of hairless mice. Journal of the Ameriean Aeademv of Dermatology 1986; 15:779 7K5. 74. Bauer EA, Sell/.er JL. F.isen A / , Retinoic acid inhibition of collagenasc and gclalinase expression in human fibroblasi cultures: evidence for a duLii mechanism. Journal of Inresngative fyermatology \9^y.»\:\(:A 169. 75, Woodley DT, Zelicksi>n .'\S, Briggaman R.A et al. Trcalincnl of pholoaged skin with topical tretinoin increases epidermaldermal anchoring librils. Journal of ihc American Medical Assoeiation 1990:263:3057 3059. 76. Kligman LH. Chen HD. Kligman AM. I'oiiical rctinoic acid enhances the repair of ultraviolet damaged connective tissue. Connective Tissue Rescareh 1984: 12: 13') 150. 77. Kligman .AM, GroveCiL. Hirose K etal. Tcipical trciiixiin for p h o t o a g e d s k i n . Journal
78. 79. 80.
81. 82, 83.
of the American
Academy
i)f
Derma-
tology 1986; 15: 836 S59.' Weiss JS. Ellis CN. Headingt
