Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 1
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Ansell, David M. Kloepper, Jennifer E. Thomason, Helen A. Paus, Ralf and Hardman, Matthew J. 2011. Exploring the “Hair Growth–Wound Healing Connection”: Anagen Phase Promotes Wound Re-Epithelialization. Journal of Investigative Dermatology, Vol. 131, Issue. 2, p. 518.


Delayed wound healing in elderly people

  • Helen A. Thomason (a1) and Matthew J. Hardman (a1)
  • DOI:
  • Published online: 02 November 2009

Our ability to heal wounds deteriorates with age, leading in many cases to a complete lack of repair and development of a chronic wound. Moreover, as the elderly population continues to grow the prevalence of non-healing chronic wounds is escalating. Cutaneous wound repair occurs through a combination of overlapping phases, including an initial inflammatory response, a proliferative phase and a final remodelling phase. In elderly subjects the inflammatory response is delayed, macrophage and fibroblast function compromised, angiogenesis reduced and re-epithelialization inhibited. Whilst a large body of historic research describes the defective processes that lead to delayed healing, only recently have the molecular mechanisms by which these defects arise begun to be elucidated. Current therapies available for treatment of chronic wounds in elderly people are surprisingly limited and generally ineffective. Thus there is an urgent need to develop new therapeutic strategies based on these recent molecular and cellular insights.

Corresponding author
Address for correspondence: Dr Matthew Hardman, Faculty of Life Sciences, A.V. Hill Building, Oxford Road, University of Manchester, Manchester M13 9PT, United Kingdom. Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2RA Clark . Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 1990; 94 (suppl): 12834S.

4A Schober , C Weber . Mechanisms of monocyte recruitment in vascular repair after injury. Antioxid Redox Signal 2005; 7: 1249–57.

6VW Ho , LM Sly . Derivation and characterization of murine alternatively activated (M2) macrophages. Methods Mol Biol 2009; 531: 173–85.

7DE Martin , MC Reece , JE Maher , SC Reese . Tissue debris at the injury site is coated by plasma fibronectin and subsequently removed by tissue macrophages. Arch Dermatol 1988; 124: 226–9.

8N Fujiwara , K Kobayashi . Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005; 4: 281–6.

9B Eckes , P Zigrino , D Kessler Fibroblast–matrix interactions in wound healing and fibrosis. Matrix Biol 2000; 19: 325–32.

10RA Clark , JQ An , D Greiling , A Khan , JE Schwarzbauer . Fibroblast migration on fibronectin requires three distinct functional domains. J Invest Dermatol 2003; 121: 695705.

11KS Midwood , Y Mao , HC Hsia , LV Valenick , JE Schwarzbauer . Modulation of cell–fibronectin matrix interactions during tissue repair. J Investig Dermatol Symp Proc 2006; 11: 73–8.

13A Desmoulière , A Geinoz , F Gabbiani , G Gabbiani . Transforming growth factor-β1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993; 122: 103–11.

14MB Vaughan , EW Howard , JJ Tomasek . Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res 2000; 257: 180–9.

15B Hinz . Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007; 127: 526–37.

16Y Barrandon , H Green . Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-α and epidermal growth factor. Cell 1987; 50: 1131–7.

17F Décline , O Okamoto , F Mallein-Gerin Keratinocyte motility induced by TGF-β1 is accompanied by dramatic changes in cellular interactions with laminin 5. Cell Motil Cytoskeleton 2003; 54: 6480.

18R Iwamoto , E Mekada . Heparin-binding EGF-like growth factor: a juxtacrine growth factor. Cytokine Growth Factor Rev 2000; 11: 335–44.

19S Werner , KG Peters , MT Longaker , F Fuller-Pace , MJ Banda , LT Williams . Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 1992; 89: 6896–900.

21I Haase , R Evans , R Pofahl , FM Watt . Regulation of keratinocyte shape, migration and wound epithelialization by IGF-1- and EGF-dependent signalling pathways. J Cell Sci 2003; 116: 3227–38.

22J Grφndahl-Hansen , LR Lund , E Ralfkiaer , V Ottevanger , K Danφ . Urokinase- and tissue-type plasminogen activators in keratinocytes during wound re-epithelialization in vivo. J Invest Dermatol 1988; 90: 790–5.

24L Ossowski , JA Aguirre-Ghiso . Urokinase receptor and integrin partnership: co-ordination of signalling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000; 12: 613–20.

25BK Pilcher , J Dumin , MJ Schwartz Keratinocyte collagenase-1 expression requires an epidermal growth factor receptor autocrine mechanism. J Biol Chem 1999; 274: 10372–81.

26LJ McCawley , LM Matrisian . Matrix metalloproteinases: they're not just for matrix anymore! Curr Opin Cell Biol 2001; 13: 534–40.

27M Seiki . The cell surface: the stage for matrix metalloproteinase regulation of migration. Curr Opin Cell Biol 2002; 14: 624–32.

28WS Krawczyk , GF Wilgram . Hemidesmosome and desmosome morphogenesis during epidermal wound healing. J Ultrastruct Res 1973; 45: 93101.

29SH Litjens , JM de Pereda , A Sonnenberg . Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol 2006; 16: 376–83.

31M Ito , Y Liu , Z Yang Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 2005; 11: 1351–4.

32J Li , YP Zhang , RS Kirsner . Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech 2003; 60: 107–14.

33PC Brooks , RA Clark , DA Cheresh . Requirement of vascular integrin α v. β3 for angiogenesis. Science 1994; 264: 569–71.

34MJ Reed , AC Corsa , SA Kudravi , RS McCormick , WT Arthur . A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells. J Cell Biochem 2000; 77: 116–26.

35MA Moses , M Marikovsky , JW Harper Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing. J Cell Biochem 1996; 60: 379–86.

36R Lobmann , A Ambrosch , G Schultz , K Waldmann , S Schiweck , H Lehnert . Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 2002; 45: 1011–6.

37RS Kurban , J Bhawan . Histologic changes in skin associated with aging. J Dermatol Surg Oncol 1990; 16: 908–14.

38MC Branchet , S Boisnic , C Frances , AM Robert . Skin thickness changes in normal aging skin. Gerontology 1990; 36: 2835.

39MC Branchet , S Boisnic , C Frances , C Lesty , L Robert . Morphometric analysis of dermal collagen fibers in normal human skin as a function of age. Arch Gerontol Geriatr 1991; 13: 114.

40S Shuster , MM Black , McVitie. The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 1975; 93: 639–43.

41M El-Domyati , S Attia , F Saleh Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Exp Dermatol 2002; 11: 398405.

43MJ Reed , NS Ferara , RB Vernon . Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of aged human donors. Mech Ageing Dev 2001; 122: 1203–20.

44W Andrew , RH Behnke , T Sato . Changes with advancing age in the cell population of the human dermis. Gerontologia 1964; 10: 119.

46W Montagna , K Carlisle . Structural changes in ageing skin. Br J Dermatol 1990; 122 (suppl 35): 6170.

47PE Pochi , JS Strauss , DT Downing . Age-related changes in sebaceous gland activity. J Invest Dermatol 1979; 73: 108–11.

48GS Ashcroft , MA Horan , MW Ferguson . Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model. J Invest Dermatol 1997; 108: 430–7.

50ME Swift , AL Burns , KL Gray , LA DiPietro . Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001; 117: 1027–35.

51D Danon , MA Kowatch , GS Roth . Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 1989; 86: 2018–20.

52A Plisko , BA Gilchrest . Growth factor responsiveness of cultured human fibroblasts declines with age. J Gerontol 1983; 38: 513–8.

53SA Bruce , SF Deamond . Longitudinal study of in vivo wound repair and in vitro cellular senescence of dermal fibroblasts. Exp Gerontol 1991; 26: 1727.

54M Freedland , S Karmiol , J Rodriguez , D Normolle , D Smith Jr, W Garner . Fibroblast responses to cytokines are maintained during aging. Ann Plast Surg 1995; 35: 290–6.

55CB Ballas , JM Davidson . Delayed wound healing in aged rats is associated with increased collagen gel remodelling and contraction by skin fibroblasts, not with differences in apoptotic or myofibroblast cell populations. Wound Repair Regen 2001; 9: 223–37.

57GS Ashcroft , MA Horan , MW Ferguson . The effects of ageing on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model. J Anat 1997; 190: 351–65.

58YP Xia , Y Zhao , JW Tyrone , A Chen , TA Mustoe . Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: implication for chronic wounds in the elderly. J Invest Dermatol 2001; 116: 50–6.

59WT Arthur , RB Vernon , EH Sage , MJ Reed . Growth factors reverse the impaired sprouting of microvessels from aged mice. Microvasc Res 1998; 55: 260–70.

60GS Ashcroft , CM Kielty , MA Horan , MW Ferguson . Age-related changes in the temporal and spatial distributions of fibrillin and elastin mRNAs and proteins in acute cutaneous wounds of healthy humans. J Pathol 1997; 183: 80–9.

61NA Halasz . Dehiscence of laparotomy wounds. Am J Surg 1968; 116: 210–4.

63P Holm-Pedersen , B Zederfeldt . Strength development of skin incisions in young and old rats. Scand J Plast Reconstr Surg 1971; 5: 712.

64LS Beck , L DeGuzman , WP Lee , Y Xu , MW Siegel , EP Amento . One systemic administration of transforming growth factor-β1 reverses age- or glucocorticoid-impaired wound healing. J Clin Invest 1993; 92: 2841–9.

65F Labrie , A Bélanger , L Cusan , JL Gomez , B Candas . Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997; 82: 2396–402.

66SJ Mills , JJ Ashworth , SC Gilliver , MJ Hardman , GS Ashcroft . The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptors. J Invest Dermatol 2005; 125: 1053–62.

67S Verdier-Sévrain , F Bonté , B Gilchrest . Biology of estrogens in skin: implications for skin aging. Exp Dermatol 2006; 15: 8394.

68GS Ashcroft , T Greenwell-Wild , MA Horan , SM Wahl , MW Ferguson . Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 1999; 155: 1137–46.

69DJ Margolis , J Knauss , W Bilker . Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet 2002; 359: 675–7.

70A Berard , SR Kahn , L Abenhaim . Is hormone replacement therapy protective for venous ulcer of the lower limbs? Pharmacoepidemol Drug Saf 2001; 10: 245–51.

71GS Ashcroft , J Dodsworth , E van Boxtel Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels. Nat Med 1997; 3: 1209–15.

72MJ Hardman , A Waite , L Zeef , M Burow , T Nakayama , GS Ashcroft . Macrophage migration inhibitory factor: a central regulator of wound healing. Am J Pathol 2005; 167: 1561–74.

73MJ Hardman , GS Ashcroft . Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly. Genome Biol 2008; 9: R80.

74E Emmerson , L Campbell , GS Ashcroft , MJ Hardman . Unique and synergistic roles for 17β-estradiol and macrophage migration inhibitory factor during cutaneous wound closure are cell type specific. Endocrinology 2009; 150: 2749–57.

75D Lundgren . Influence of estrogen and progesterone on exudation, inflammatory cell migration and granulation tissue formation in preformed cavities. Scand J Plast Reconstr Surg 1973; 7: 1014.

76CE Routley , GS Ashcroft . Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair Regen 2009; 17: 4250.

77GS Ashcroft , SJ Mills , K Lei Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest 2003 May; 111: 1309–18.

78RJ Taylor , AD Taylor , JV Smyth . Using an artificial neural network to predict healing times and risk factors for venous leg ulcers. J Wound Care 2002; 11: 101–5.

79GS Ashcroft , SJ Mills . Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest 2002; 110: 615–24.

80GS Ashcroft , SJ Mills , KC Flanders Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen 2003; 11: 468–73.

81SC Gilliver , JP Ruckshanthi , MJ Hardman , T Nakayama , GS Ashcroft . Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology 2008; 149: 5747–57.

82SC Gilliver , JP Ruckshanthi , MJ Hardman , LA Zeef , GS Ashcroft . 5α-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization. J Pathol 2009; 217: 7382.

85K Kerlikowske , DL Miglioretti , DS Buist Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst 2007; 99: 1335–39.

86PM Ravdin , KA Cronin , N Howlader The decrease in breast cancer incidence in 2003 in the United States. N Engl J Med 2007; 356: 1670–74.

87M Kumle . Declining breast cancer incidence and decreased HRT use. Lancet 2008; 372: 608–10.

88AZ Bluming , C Tavris . Hormone replacement therapy: real concerns and false alarms. Cancer J 2009; 15: 93104.

89MJ Hardman , E Emmerson , L Campbell , GS Ashcroft . Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology 2008; 149: 551–7.

90P Collins , L Mosca , MJ Geiger Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation 2009; 119: 922–30.

91H Sumino , S Ichikawa , S Kasama Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women. Maturitas 2009; 62: 53–7.

92L Gennari . Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother 2009; 10: 2209–20.

93AW Kung , EY Chu , L Xu . Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. Expert Opin Pharmacother 2009; 10: 1377–85.

94A Nath , R Sitruk-Ware . Pharmacology and clinical applications of selective estrogen receptor modulators. Climacteric 2009; 12: 188205.

96M Shah , DM Foreman , MW Ferguson . Control of scarring in adult wounds by neutralising antibody to transforming growth factor β. Lancet 1992; 339: 213–4.

99DJ Margolis , T Cromblehome , M Herlyn Clinical protocol. Phase I trial to evaluate the safety of H5.020CMV.PDGF-β and limb compression bandage for the treatment of venous leg ulcer: trial A. Hum Gene Ther 2004; 15: 1003–19.

101RE Horch , J Kopp , U Kneser , J Beier , AD Bach . Tissue engineering of cultured skin substitutes. J Cell Mol Med 2005; 9: 592608.

102K Hata . Current issues regarding skin substitutes using living cells as industrial materials. J Artif Organs 2007; 10: 129–32.

103TL Dinh , A Veves . The efficacy of Apligraf in the treatment of diabetic foot ulcers. Plast Reconstr Surg 2006; 117 (7 suppl): 15257S; discussion 158–59S.

104M Edmonds . Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds 2009; 8: 11–8.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Reviews in Clinical Gerontology
  • ISSN: 0959-2598
  • EISSN: 1469-9036
  • URL: /core/journals/reviews-in-clinical-gerontology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *