, Volume 13, Issue 1, pp 3–20 | Cite as

The role of estrogen deficiency in skin ageing and wound healing

  • Elaine Emmerson
  • Matthew J. HardmanEmail author
Review Article


The links between hormonal signalling and lifespan have been well documented in a range of model organisms. For example, in C. elegans or D. melanogaster, lifespan can be modulated by ablating germline cells, or manipulating reproductive history or pregnenolone signalling. In mammalian systems, however, hormonal contribution to longevity is less well understood. With increasing age human steroid hormone profiles change substantially, particularly following menopause in women. This article reviews recent links between steroid sex hormones and ageing, with special emphasis on the skin and wound repair. Estrogen, which substantially decreases with advancing age in both males and females, protects against multiple aspects of cellular ageing in rodent models, including oxidative damage, telomere shortening and cellular senescence. Estrogen’s effects are particularly pronounced in the skin where cutaneous changes post-menopause are well documented, and can be partially reversed by classical Hormone Replacement Therapy (HRT). Our research shows that while chronological ageing has clear effects on skin wound healing, falling estrogen levels are the principle mediator of these effects. Thus, both HRT and topical estrogen replacement substantially accelerate healing in elderly humans, but are associated with unwanted deleterious effects, particularly cancer promotion. In fact, much current research effort is being invested in exploring the therapeutic potential of estrogen signalling manipulation to reverse age-associated pathology in peripheral tissues. In the case of the skin the differential targeting of estrogen receptors to promote healing in aged subjects is a real therapeutic possibility.


Estrogen Ageing Skin Wound healing 



Dr Emmerson is the David Hammond Charitable Trust Research Associate (The Healing Foundation) and recipient of the BSRA 2010 Korenchevsky award. Dr Hardman is the Edmund de Rothschild Senior Fellow in Ageing Research (Research Into Ageing; Age UK).


  1. Aertgeerts J (1974) Effect of oral estrogens on the skin of the woman in post-menopause or after castration. Ther Ggw 113(10):1739–1748PubMedGoogle Scholar
  2. Ali S, Coombes RC (2000) Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia 5(3):271–281PubMedGoogle Scholar
  3. Ali SS, Xiong C, Lucero J, Behrens MM, Dugan LL, Quick KL (2006) Gender differences in free radical homeostasis during aging: shorter-lived female c57bl6 mice have increased oxidative stress. Aging Cell 5(6):565–574PubMedGoogle Scholar
  4. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89(21):10114–10118PubMedGoogle Scholar
  5. Aloisi AM, Pari G, Ceccarelli I, Vecchi I, Ietta F, Lodi L, Paulesu L (2005) Gender-related effects of chronic non-malignant pain and opioid therapy on plasma levels of macrophage migration inhibitory factor (mif). Pain 115(1–2):142–151PubMedGoogle Scholar
  6. Arai N, Strom A, Rafter JJ, Gustafsson JA (2000) Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein. Biochem Biophys Res Commun 270(2):425–431PubMedGoogle Scholar
  7. Arantes-Oliveira N, Apfeld J, Dillin A, Kenyon C (2002) Regulation of life-span by germ-line stem cells in caenorhabditis elegans. Science 295(5554):502–505PubMedGoogle Scholar
  8. Argyris TS (1983) The effect of aging on epidermal mass in balb/c female mice. Mech Ageing Dev 22(3–4):347–354PubMedGoogle Scholar
  9. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE (2009) Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev (3):CD004425Google Scholar
  10. Asdell SA, Joshi SR (1976) Reproduction and longevity in the hamster and rat. Biol Reprod 14(4):478–480PubMedGoogle Scholar
  11. Ashcroft GS, Mills SJ (2002) Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest 110(5):615–624PubMedGoogle Scholar
  12. Ashcroft GS, Dodsworth J, van Boxtel E, Tarnuzzer RW, Horan MA, Schultz GS, Ferguson MW (1997a) Estrogen accelerates cutaneous wound healing associated with an increase in tgf-beta1 levels. Nat Med 3(11):1209–1215PubMedGoogle Scholar
  13. Ashcroft GS, Herrick SE, Tarnuzzer RW, Horan MA, Schultz GS, Ferguson MW (1997b) Human ageing impairs injury-induced in vivo expression of tissue inhibitor of matrix metalloproteinases (timp)-1 and -2 proteins and mrna. J Pathol 183(2):169–176PubMedGoogle Scholar
  14. Ashcroft GS, Horan MA, Ferguson MW (1997c) 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 108(4):430–437PubMedGoogle Scholar
  15. Ashcroft GS, Horan MA, Ferguson MW (1997d) The effects of ageing on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model. J Anat 190(Pt 3):351–365PubMedGoogle Scholar
  16. Ashcroft GS, Horan MA, Herrick SE, Tarnuzzer RW, Schultz GS, Ferguson MW (1997e) Age-related differences in the temporal and spatial regulation of matrix metalloproteinases (mmps) in normal skin and acute cutaneous wounds of healthy humans. Cell Tissue Res 290(3):581–591PubMedGoogle Scholar
  17. Ashcroft GS, Kielty CM, Horan MA, Ferguson MW (1997f) 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 183(1):80–89PubMedGoogle Scholar
  18. Ashcroft GS, Horan MA, Ferguson MW (1998) Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 78(1):47–58PubMedGoogle Scholar
  19. Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW (1999) Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 155(4):1137–1146PubMedGoogle Scholar
  20. Ashcroft GS, Mills SJ, Lei K, Gibbons L, Jeong MJ, Taniguchi M, Burow M, Horan MA, Wahl SM, Nakayama T (2003) Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest 111(9):1309–1318PubMedGoogle Scholar
  21. Ashworth JJ, Smyth JV, Pendleton N, Horan M, Payton A, Worthington J, Ollier WE, Ashcroft GS (2005) The dinucleotide (ca) repeat polymorphism of estrogen receptor beta but not the dinucleotide (ta) repeat polymorphism of estrogen receptor alpha is associated with venous ulceration. J Steroid Biochem Mol Biol 97(3):266–270PubMedGoogle Scholar
  22. Ashworth JJ, Smyth JV, Pendleton N, Horan M, Payton A, Worthington J, Ollier WE, Ashcroft GS (2008) Polymorphisms spanning the on exon and promoter of the estrogen receptor-beta (erbeta) gene esr2 are associated with venous ulceration. Clin Genet 73(1):55–61PubMedGoogle Scholar
  23. Atteritano M, Pernice F, Mazzaferro S, Mantuano S, Frisina A, D’Anna R, Cannata ML, Bitto A, Squadrito F, Frisina N, Buemi M (2008) Effects of phytoestrogen genistein on cytogenetic biomarkers in postmenopausal women: 1 year randomized, placebo-controlled study. Eur J Pharmacol 589(1–3):22–26PubMedGoogle Scholar
  24. Aviv A, Shay J, Christensen K, Wright W (2005) The longevity gender gap: are telomeres the explanation? Sci Aging Knowledge Environ 2005(23):pe16PubMedGoogle Scholar
  25. Aviv A, Valdes A, Gardner JP, Swaminathan R, Kimura M, Spector TD (2006) Menopause modifies the association of leukocyte telomere length with insulin resistance and inflammation. J Clin Endocrinol Metab 91(2):635–640PubMedGoogle Scholar
  26. Baeza I, Fdez-Tresguerres J, Ariznavarreta C, De la Fuente M (2010) Effects of growth hormone, melatonin, oestrogens and phytoestrogens on the oxidized glutathione (gssg)/reduced glutathione (gsh) ratio and lipid peroxidation in aged ovariectomized rats. Biogerontology 11(6):687–701PubMedGoogle Scholar
  27. Barrett-Connor E (1995) Postmenopausal estrogen and heart disease. Atherosclerosis 118(Suppl):S7–S10PubMedGoogle Scholar
  28. Battegay EJ, Rupp J, Iruela-Arispe L, Sage EH, Pech M (1994) Pdgf-bb modulates endothelial proliferation and angiogenesis in vitro via pdgf beta-receptors. J Cell Biol 125(4):917–928PubMedGoogle Scholar
  29. Bayne S, Jones ME, Li H, Pinto AR, Simpson ER, Liu JP (2008) Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice. Cell Res 18(11):1141–1150PubMedGoogle Scholar
  30. Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78(2):547–581PubMedGoogle Scholar
  31. Berard A, Kahn SR, Abenhaim L (2001) Is hormone replacement therapy protective for venous ulcer of the lower limbs? Pharmacoepidemiol Drug Saf 10(3):245–251PubMedGoogle Scholar
  32. Berneburg M, Grether-Beck S, Kurten V, Ruzicka T, Briviba K, Sies H, Krutmann J (1999) Singlet oxygen mediates the uva-induced generation of the photoaging-associated mitochondrial common deletion. J Biol Chem 274(22):15345–15349PubMedGoogle Scholar
  33. Bhattacharyya TK, Thomas JR (2004) Histomorphologic changes in aging skin: observations in the cba mouse model. Arch Facial Plast Surg 6(1):21–25PubMedGoogle Scholar
  34. Bhattacharyya TK, Merz M, Thomas JR (2005) Modulation of cutaneous aging with calorie restriction in Fischer 344 rats: a histological study. Arch Facial Plast Surg 7(1):12–16PubMedGoogle Scholar
  35. Boldt J, Huttner I, Suttner S, Kumle B, Piper SN, Berchthold G (2001) Changes of haemostasis in patients undergoing major abdominal surgery—is there a difference between elderly and younger patients? Br J Anaesth 87(3):435–440PubMedGoogle Scholar
  36. Borras C, Sastre J, Garcia-Sala D, Lloret A, Pallardo FV, Vina J (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34(5):546–552PubMedGoogle Scholar
  37. Borras C, Gambini J, Gomez-Cabrera MC, Sastre J, Pallardo FV, Mann GE, Vina J (2005) 17beta-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the erk1 and erk2[mapk]/nfkappab cascade. Aging Cell 4(3):113–118PubMedGoogle Scholar
  38. Borras C, Gambini J, Gomez-Cabrera MC, Sastre J, Pallardo FV, Mann GE, Vina J (2006) Genistein, a soy isoflavone, up-regulates expression of antioxidant genes: involvement of estrogen receptors, erk1/2, and nfkappab. Faseb J 20(12):2136–2138PubMedGoogle Scholar
  39. Boyd AS, Morris LF, Phillips CM, Menter MA (1996) Psoriasis and pregnancy: hormone and immune system interaction. Int J Dermatol 35(3):169–172PubMedGoogle Scholar
  40. Brand RM, Jendrzejewski JL (2008) Topical treatment with (−)-epigallocatechin-3-gallate and genistein after a single uv exposure can reduce skin damage. J Dermatol Sci 50(1):69–72PubMedGoogle Scholar
  41. Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB (1997) Tissue distribution of estrogen receptors alpha (er-alpha) and beta (er-beta) mrna in the midgestational human fetus. J Clin Endocrinol Metab 82(10):3509–3512PubMedGoogle Scholar
  42. Braverman IM, Fonferko E (1982) Studies in cutaneous aging: I. The elastic fiber network. J Invest Dermatol 78(5):434–443PubMedGoogle Scholar
  43. Brincat MP (2000) Hormone replacement therapy and the skin. Maturitas 35(2):107–117PubMedGoogle Scholar
  44. Brincat M, Moniz CJ, Studd JW, Darby A, Magos A, Emburey G, Versi E (1985) Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol 92(3):256–259PubMedGoogle Scholar
  45. Brincat M, Versi E, Moniz CF, Magos A, de Trafford J, Studd JW (1987) Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol 70(1):123–127PubMedGoogle Scholar
  46. Broue F, Liere P, Kenyon C, Baulieu EE (2007) A steroid hormone that extends the lifespan of caenorhabditis elegans. Aging Cell 6(1):87–94PubMedGoogle Scholar
  47. Bullough HF (1947) Epidermal thickness following oestrone injections in the mouse. Nature 159(4029):101PubMedGoogle Scholar
  48. Bulun SE, Zeitoun K, Sasano H, Simpson ER (1999) Aromatase in aging women. Semin Reprod Endocrinol 17(4):349–358PubMedGoogle Scholar
  49. Cai Q, Shu XO, Jin F, Dai Q, Wen W, Cheng JR, Gao YT, Zheng W (2003) Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: results from the shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 12(9):853–859PubMedGoogle Scholar
  50. Calleja M, Pena P, Ugalde C, Ferreiro C, Marco R, Garesse R (1993) Mitochondrial DNA remains intact during drosophila aging, but the levels of mitochondrial transcripts are significantly reduced. J Biol Chem 268(25):18891–18897PubMedGoogle Scholar
  51. Calmels P, Vico L, Alexandre C, Minaire P (1995) Cross-sectional study of muscle strength and bone mineral density in a population of 106 women between the ages of 44 and 87 years: relationship with age and menopause. Eur J Appl Physiol Occup Physiol 70(2):180–186PubMedGoogle Scholar
  52. Cameron IL (1972) Cell proliferation and renewal in aging mice. J Gerontol 27(2):162–172PubMedGoogle Scholar
  53. Campbell L, Emmerson E, Davies F, Gilliver SC, Krust A, Chambon P, Ashcroft GS, Hardman MJ (2010) Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of it’s anti-inflammatory activities. J Exp Med 207(9):1825–1833PubMedGoogle Scholar
  54. Carcenac G, Herard ME, Kergoat MJ, Lajeunesse Y, Champoux N, Barsauskas A, Kergoat H (2009) Assessment of visual function in institutionalized elderly patients. J Am Med Dir Assoc 10(1):45–49PubMedGoogle Scholar
  55. Cargill SL, Carey JR, Muller HG, Anderson G (2003) Age of ovary determines remaining life expectancy in old ovariectomized mice. Aging Cell 2(3):185–190PubMedGoogle Scholar
  56. Castelo-Branco C, Duran M, Gonzalez-Merlo J (1992) Skin collagen changes related to age and hormone replacement therapy. Maturitas 15(2):113–119PubMedGoogle Scholar
  57. Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW (1976) Hormonal profiles after the menopause. Br Med J 2(6039):784–787PubMedGoogle Scholar
  58. Chen W, Zouboulis CC, Fritsch M, Blume-Peytavi U, Kodelja V, Goerdt S, Luu-The V, Orfanos CE (1998) Evidence of heterogeneity and quantitative differences of the type 1 5alpha-reductase expression in cultured human skin cells—evidence of its presence in melanocytes. J Invest Dermatol 110(1):84–89PubMedGoogle Scholar
  59. Chen W, Thiboutot D, Zouboulis CC (2002) Cutaneous androgen metabolism: basic research and clinical perspectives. J Invest Dermatol 119(5):992–1007PubMedGoogle Scholar
  60. Chiu TM, Huang CC, Lin TJ, Fang JY, Wu NL, Hung CF (2009) In vitro and in vivo anti-photoaging effects of an isoflavone extract from soybean cake. J Ethnopharmacol 126(1):108–113PubMedGoogle Scholar
  61. Cho JL, Allanson M, Domanski D, Arun SJ, Reeve VE (2008) Estrogen receptor-beta signaling protects epidermal cytokine expression and immune function from uvb-induced impairment in mice. Photochem Photobiol Sci 7(1):120–125PubMedGoogle Scholar
  62. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH (1987) Menopause and the risk of coronary heart disease in women. N Engl J Med 316(18):1105–1110PubMedGoogle Scholar
  63. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (1997) Tissue distribution and quantitative analysis of estrogen receptor-alpha (eralpha) and estrogen receptor-beta (erbeta) messenger ribonucleic acid in the wild-type and eralpha-knockout mouse. Endocrinology 138(11):4613–4621PubMedGoogle Scholar
  64. Creidi P, Faivre B, Agache P, Richard E, Haudiquet V, Sauvanet JP (1994) Effect of a conjugated oestrogen (premarin) cream on ageing facial skin. A comparative study with a placebo cream. Maturitas 19(3):211–223PubMedGoogle Scholar
  65. D’Anna R, Cannata ML, Atteritano M, Cancellieri F, Corrado F, Baviera G, Triolo O, Antico F, Gaudio A, Frisina N, Bitto A, Polito F, Minutoli L, Altavilla D, Marini H, Squadrito F (2007) Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study. Menopause 14(4):648–655PubMedGoogle Scholar
  66. De Paula ML, Rodrigues DH, Teixeira HC, Barsante MM, Souza MA, Ferreira AP (2008) Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis. Int Immunopharmacol 8(9):1291–1297PubMedGoogle Scholar
  67. Dimri GP, Hara E, Campisi J (1994) Regulation of two e2f-related genes in presenescent and senescent human fibroblasts. J Biol Chem 269(23):16180–16186PubMedGoogle Scholar
  68. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92(20):9363–9367PubMedGoogle Scholar
  69. Dumont M, Luu-The V, Dupont E, Pelletier G, Labrie F (1992) Characterization, expression, and immunohistochemical localization of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase in human skin. J Invest Dermatol 99(4):415–421PubMedGoogle Scholar
  70. Dunna SF, Finlay AY (1989) Psoriasis: improvement during and worsening after pregnancy. Br J Dermatol 120(4):584PubMedGoogle Scholar
  71. Eicheler W, Dreher M, Hoffmann R, Happle R, Aumuller G (1995) Immunohistochemical evidence for differential distribution of 5 alpha-reductase isoenzymes in human skin. Br J Dermatol 133(3):371–376PubMedGoogle Scholar
  72. Emmerson E, Campbell L, Ashcroft GS, Hardman MJ (2009) Unique and synergistic roles for 17beta-estradiol and macrophage migration inhibitory factor during cutaneous wound closure are cell type specific. Endocrinology 150(6):2749–2757PubMedGoogle Scholar
  73. Emmerson E, Campbell L, Ashcroft GS, Hardman MJ (2010) The phytoestrogen genistein promotes wound healing by multiple independent mechanisms. Mol Cell Endocrinol 321(2):184–193PubMedGoogle Scholar
  74. Evans WJ (2010) Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr 91(4):1123S–1127SPubMedGoogle Scholar
  75. Evans JR, Schwartz SD, McHugh JD, Thamby-Rajah Y, Hodgson SA, Wormald RP, Gregor ZJ (1998) Systemic risk factors for idiopathic macular holes: a case-control study. Eye (Lond) 12(Pt 2):256–259Google Scholar
  76. Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML (1999) Functional estrogen receptor beta in colon cancer cells. Biochem Biophys Res Commun 261(2):521–527PubMedGoogle Scholar
  77. Flatt T, Min KJ, D’Alterio C, Villa-Cuesta E, Cumbers J, Lehmann R, Jones DL, Tatar M (2008) Drosophila germ-line modulation of insulin signaling and lifespan. Proc Natl Acad Sci USA 105(17):6368–6373PubMedGoogle Scholar
  78. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60(2):245–248PubMedGoogle Scholar
  79. Frasor J, Stossi F, Danes JM, Komm B, Lyttle CR, Katzenellenbogen BS (2004) Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res 64(4):1522–1533PubMedGoogle Scholar
  80. Fuchs KO, Solis O, Tapawan R, Paranjpe J (2003) The effects of an estrogen and glycolic acid cream on the facial skin of postmenopausal women: a randomized histologic study. Cutis 71(6):481–488PubMedGoogle Scholar
  81. Fukaya S, Iwamoto T, Kin K, Takasaki M (2000) Factors influencing platelet function in elderly patients with chronic phase thrombotic diseases. Nippon Ronen Igakkai Zasshi 37(8):619–626PubMedGoogle Scholar
  82. Gal P, Novotny M, Vasilenko T, Depta F, Sulla I, Tomori Z (2010) Decrease in wound tensile strength following post-surgical estrogen replacement therapy in ovariectomized rats during the early phase of healing is mediated via er-alpha rather than er-beta: a preliminary report. J Surg Res 159(1):e25–e28PubMedGoogle Scholar
  83. Gates BJ, Sonnett TE, Duvall CA, Dobbins EK (2009) Review of osteoporosis pharmacotherapy for geriatric patients. Am J Geriatr Pharmacother 7(6):293–323PubMedGoogle Scholar
  84. Gerisch B, Antebi A (2004) Hormonal signals produced by daf-9/cytochrome p450 regulate c. Elegans dauer diapause in response to environmental cues. Development 131(8):1765–1776PubMedGoogle Scholar
  85. Gerisch B, Weitzel C, Kober-Eisermann C, Rottiers V, Antebi A (2001) A hormonal signaling pathway influencing c. Elegans metabolism, reproductive development, and life span. Dev Cell 1(6):841–851PubMedGoogle Scholar
  86. Giangreco A, Qin M, Pintar JE, Watt FM (2008) Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell 7(2):250–259PubMedGoogle Scholar
  87. Gilchrest BA (1983) In vitro assessment of keratinocyte aging. J Invest Dermatol 81(1 Suppl):184s–189sPubMedGoogle Scholar
  88. Gilchrest BA, Murphy GF, Soter NA (1982a) Effect of chronologic aging and ultraviolet irradiation on langerhans cells in human epidermis. J Invest Dermatol 79(2):85–88PubMedGoogle Scholar
  89. Gilchrest BA, Stoff JS, Soter NA (1982b) Chronologic aging alters the response to ultraviolet-induced inflammation in human skin. J Invest Dermatol 79(1):11–15PubMedGoogle Scholar
  90. Gilchrest BA, Szabo G, Flynn E, Goldwyn RM (1983) Chronologic and actinically induced aging in human facial skin. J Invest Dermatol 80 Suppl:81s–85sPubMedGoogle Scholar
  91. Gilliver SC, Wu F, Ashcroft GS (2003) Regulatory roles of androgens in cutaneous wound healing. Thromb Haemost 90(6):978–985PubMedGoogle Scholar
  92. Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS (2006) Androgens modulate the inflammatory response during acute wound healing. J Cell Sci 119(Pt 4):722–732PubMedGoogle Scholar
  93. Gilliver SC, Ruckshanthi JP, Hardman MJ, Zeef LA, Ashcroft GS (2009) 5alpha-dihydrotestosterone (dht) retards wound closure by inhibiting re-epithelialization. J Pathol 217(1):73–82PubMedGoogle Scholar
  94. Goldzieher JW (1949) The direct effect of steroids on the senile human skin. J Gerontol 4(2):104–112PubMedGoogle Scholar
  95. Gragnani A, Warde M, Furtado F, Ferreira LM (2009) Topical tamoxifen therapy in hypertrophic scars or keloids in burns. Arch Dermatol Res 302(1):1–4PubMedGoogle Scholar
  96. Gurwitz JH (2005) The age/gender interface in geriatric pharmacotherapy. J Womens Health (Larchmt) 14(1):68–72Google Scholar
  97. Haratake A, Uchida Y, Mimura K, Elias PM, Holleran WM (1997) Intrinsically aged epidermis displays diminished uvb-induced alterations in barrier function associated with decreased proliferation. J Invest Dermatol 108(3):319–323PubMedGoogle Scholar
  98. Hardman MJ, Ashcroft GS (2008) Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly. Genome Biol 9(5):R80PubMedGoogle Scholar
  99. Hardman MJ, Waite A, Zeef L, Burow M, Nakayama T, Ashcroft GS (2005) Macrophage migration inhibitory factor: a central regulator of wound healing. Am J Pathol 167(6):1561–1574PubMedGoogle Scholar
  100. Hardman MJ, Emmerson E, Campbell L, Ashcroft GS (2008) Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology 149(2):551–557PubMedGoogle Scholar
  101. Harley CB (1991) Telomere loss: mitotic clock or genetic time bomb? Mutat Res 256(2–6):271–282PubMedGoogle Scholar
  102. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300PubMedGoogle Scholar
  103. Havlikova H, Hill M, Hampl R, Starka L (2002) Sex- and age-related changes in epitestosterone in relation to pregnenolone sulfate and testosterone in normal subjects. J Clin Endocrinol Metab 87(5):2225–2231PubMedGoogle Scholar
  104. Hazelton GA, Lang CA (1984) Glutathione levels during the mosquito life span with emphasis on senescence. Proc Soc Exp Biol Med 176(3):249–256PubMedGoogle Scholar
  105. Hederstierna C, Hultcrantz M, Collins A, Rosenhall U (2007) Hearing in women at menopause. Prevalence of hearing loss, audiometric configuration and relation to hormone replacement therapy. Acta Otolaryngol 127(2):149–155PubMedGoogle Scholar
  106. Hederstierna C, Hultcrantz M, Collins A, Rosenhall U (2010) The menopause triggers hearing decline in healthy women. Hear Res 259(1–2):31–35PubMedGoogle Scholar
  107. Henneman DH (1968) Effect of estrogen on in vivo and in vitro collagen biosynthesis and maturation in old and young female guinea pigs. Endocrinology 83(4):678–690PubMedGoogle Scholar
  108. Herndon JG, Tigges J, Anderson DC, Klumpp SA, McClure HM (1999) Brain weight throughout the life span of the chimpanzee. J Comp Neurol 409(4):567–572PubMedGoogle Scholar
  109. Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M (1997) Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest 77(3):281–288PubMedGoogle Scholar
  110. Herynk MH, Fuqua SA (2004) Estrogen receptor mutations in human disease. Endocr Rev 25(6):869–898PubMedGoogle Scholar
  111. Hill MW (1988) Influence of age on the morphology and transit time of murine stratified squamous epithelia. Arch Oral Biol 33(4):221–229PubMedGoogle Scholar
  112. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) Igf-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421(6919):182–187PubMedGoogle Scholar
  113. Hosono R, Nishimoto S, Kuno S (1989) Alterations of life span in the nematode caenorhabditis elegans under monoxenic culture conditions. Exp Gerontol 24(3):251–264PubMedGoogle Scholar
  114. Hsin H, Kenyon C (1999) Signals from the reproductive system regulate the lifespan of c. Elegans. Nature 399(6734):362–366PubMedGoogle Scholar
  115. Hu SK, Mitcho YL, Rath NC (1988) Effect of estradiol on interleukin 1 synthesis by macrophages. Int J Immunopharmacol 10(3):247–252PubMedGoogle Scholar
  116. Hughes SV, Robinson E, Bland R, Lewis HM, Stewart PM, Hewison M (1997) 1,25-dihydroxyvitamin d3 regulates estrogen metabolism in cultured keratinocytes. Endocrinology 138(9):3711–3718PubMedGoogle Scholar
  117. Humphries S, Stevens DJ (2001) Reproductive biology. Out with a bang. Nature 410(6830):758–759PubMedGoogle Scholar
  118. Imanishi T, Hano T, Nishio I (2005a) Estrogen reduces angiotensin ii-induced acceleration of senescence in endothelial progenitor cells. Hypertens Res 28(3):263–271PubMedGoogle Scholar
  119. Imanishi T, Hano T, Nishio I (2005b) Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity. J Hypertens 23(9):1699–1706PubMedGoogle Scholar
  120. Iversen OH, Schjoelberg AR (1984) Age-related changes of epidermal cell kinetics in the hairless mouse. Virchows Arch B Cell Pathol Incl Mol Pathol 46(1–2):135–143PubMedGoogle Scholar
  121. Jacobsen BK, Nilssen S, Heuch I, Kvale G (1997) Does age at natural menopause affect mortality from ischemic heart disease? J Clin Epidemiol 50(4):475–479PubMedGoogle Scholar
  122. Jia K, Albert PS, Riddle DL (2002) Daf-9, a cytochrome p450 regulating c. Elegans larval development and adult longevity. Development 129(1):221–231PubMedGoogle Scholar
  123. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A c. Elegans mutant that lives twice as long as wild type. Nature 366(6454):461–464PubMedGoogle Scholar
  124. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) Daf-2, an insulin receptor-like gene that regulates longevity and diapause in caenorhabditis elegans. Science 277(5328):942–946PubMedGoogle Scholar
  125. Klass MR (1977) Aging in the nematode caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev 6(6):413–429PubMedGoogle Scholar
  126. Kligman AM, Koblenzer C (1997) Demographics and psychological implications for the aging population. Dermatol Clin 15(4):549–553PubMedGoogle Scholar
  127. Kovacs EJ, Faunce DE, Ramer-Quinn DS, Mott FJ, Dy PW, Frazier-Jessen MR (1996) Estrogen regulation of je/mcp-1 mrna expression in fibroblasts. J Leukoc Biol 59(4):562–568PubMedGoogle Scholar
  128. Krunic D, Moshir S, Greulich-Bode KM, Figueroa R, Cerezo A, Stammer H, Stark HJ, Gray SG, Nielsen KV, Hartschuh W, Boukamp P (2009) Tissue context-activated telomerase in human epidermis correlates with little age-dependent telomere loss. Biochim Biophys Acta 1792(4):297–308PubMedGoogle Scholar
  129. Ku HH, Brunk UT, Sohal RS (1993) Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med 15(6):621–627PubMedGoogle Scholar
  130. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93(12):5925–5930PubMedGoogle Scholar
  131. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138(3):863–870PubMedGoogle Scholar
  132. Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB (2002) Dementia and alzheimer disease incidence: a prospective cohort study. Arch Neurol 59(11):1737–1746PubMedGoogle Scholar
  133. Labrie F, Belanger A, Cusan L, Gomez JL, Candas B (1997) Marked decline in serum concentrations of adrenal c19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82(8):2396–2402PubMedGoogle Scholar
  134. Labrie F, Martel C, Balser J (2011) Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: role of the ovary? Menopause 18(1):30–43PubMedGoogle Scholar
  135. Lane MA, Ball SS, Ingram DK, Cutler RG, Engel J, Read V, Roth GS (1995) Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points. Am J Physiol 268(5 Pt 1):E941–E948PubMedGoogle Scholar
  136. Larsen PL, Albert PS, Riddle DL (1995) Genes that regulate both development and longevity in caenorhabditis elegans. Genetics 139(4):1567–1583PubMedGoogle Scholar
  137. Lavker RM (1979) Structural alterations in exposed and unexposed aged skin. J Invest Dermatol 73(1):59–66PubMedGoogle Scholar
  138. Lenhardt R, Hopf HW, Marker E, Akca O, Kurz A, Scheuenstuhl H, Sessler DI (2000) Perioperative collagen deposition in elderly and young men and women. Arch Surg 135(1):71–74PubMedGoogle Scholar
  139. Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A (2003) Genetic mouse models of extended lifespan. Exp Gerontol 38(11–12):1353–1364PubMedGoogle Scholar
  140. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L (2002) Calorie restriction extends saccharomyces cerevisiae lifespan by increasing respiration. Nature 418(6895):344–348PubMedGoogle Scholar
  141. Lindblad U, Langer RD, Wingard DL, Thomas RG, Barrett-Connor EL (2001) Metabolic syndrome and ischemic heart disease in elderly men and women. Am J Epidemiol 153(5):481–489PubMedGoogle Scholar
  142. Lindstedt E, Sandblom P (1975) Wound healing in man: tensile strength of healing wounds in some patient groups. Ann Surg 181(6):842–846PubMedGoogle Scholar
  143. Ling S, Zhou L, Li H, Dai A, Liu JP, Komesaroff PA, Sudhir K (2006) Effects of 17beta-estradiol on growth and apoptosis in human vascular endothelial cells: influence of mechanical strain and tumor necrosis factor-alpha. Steroids 71(9):799–808PubMedGoogle Scholar
  144. Loeser AA (1937) The resorption and action of follicular hormone rubbed into the skin. J Obstet Gynaecol Br Emp 44:710Google Scholar
  145. Lokkegaard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B, Pedersen AT (2006) The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy. Maturitas 53(2):226–233PubMedGoogle Scholar
  146. Longcope C (1971) Metabolic clearance and blood production rates of estrogens in postmenopausal women. Am J Obstet Gynecol 111(6):778–781PubMedGoogle Scholar
  147. Lopez-Torres M, Perez-Campo R, Rojas C, Cadenas S, Barja G (1993) Maximum life span in vertebrates: relationship with liver antioxidant enzymes, glutathione system, ascorbate, urate, sensitivity to peroxidation, true malondialdehyde, in vivo H2O2, and basal and maximum aerobic capacity. Mech Ageing Dev 70(3):177–199PubMedGoogle Scholar
  148. Lundgren D (1973) Influence of estrogen and progesterone on exudation, inflammatory cell migration and granulation tissue formation in preformed cavities. Scand J Plast Reconstr Surg 7(1):10–14PubMedGoogle Scholar
  149. Lye M, Donnellan C (2000) Heart disease in the elderly. Heart 84(5):560–566PubMedGoogle Scholar
  150. Magnusson U, Einarsson S (1990) Effects of exogenous oestradiol on the number and functional capacity of circulating mononuclear and polymorphonuclear leukocytes in the sow. Vet Immunol Immunopathol 25(3):235–247PubMedGoogle Scholar
  151. Mair W, Goymer P, Pletcher SD, Partridge L (2003) Demography of dietary restriction and death in drosophila. Science 301(5640):1731–1733PubMedGoogle Scholar
  152. Mak HY, Ruvkun G (2004) Intercellular signaling of reproductive development by the c. Elegans daf-9 cytochrome p450. Development 131(8):1777–1786PubMedGoogle Scholar
  153. Makrantonaki E, Vogel K, Fimmel S, Oeff M, Seltmann H, Zouboulis CC (2008) Interplay of igf-i and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro. Exp Gerontol 43(10):939–946PubMedGoogle Scholar
  154. Margolis DJ, Knauss J, Bilker W (2002) Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet 359(9307):675–677PubMedGoogle Scholar
  155. Marini H, Polito F, Altavilla D, Irrera N, Minutoli L, Calo M, Adamo EB, Vaccaro M, Squadrito F, Bitto A (2010) Genistein aglycone improves skin repair in an incisional model of wound healing: a comparison with raloxifene and oestradiol in ovariectomized rats. Br J Pharmacol 160(5):1185–1194PubMedGoogle Scholar
  156. Mason JB, Cargill SL, Anderson GB, Carey JR (2009) Transplantation of young ovaries to old mice increased life span in transplant recipients. J Gerontol A Biol Sci Med Sci 64(12):1207–1211PubMedGoogle Scholar
  157. Matsumoto T (2006) Selective estrogen receptor modulators (serms). Clin Calcium 16(9):100–105Google Scholar
  158. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of the lifespan and upon the ultimate body size. J Nutr 10:63–79Google Scholar
  159. McCulloch D, Gems D (2003) Evolution of male longevity bias in nematodes. Aging Cell 2(3):165–173PubMedGoogle Scholar
  160. Melton LJ III, Chrischilles EA, Cooper C, Lane AW, Riggs BL (1992) Perspective. How many women have osteoporosis? J Bone Miner Res 7(9):1005–1010PubMedGoogle Scholar
  161. Mendoza CB Jr, Postlethwait RW, Johnson WD (1970) Veterans administration cooperative study of surgery for duodenal ulcer. Ii. Incidence of wound disruption following operation. Arch Surg 101(3):396–398PubMedGoogle Scholar
  162. Mets T, Bekaert E, Verdonk G (1983) Similarity between in vitro and in vivo cellular aging. Mech Ageing Dev 22(1):71–78PubMedGoogle Scholar
  163. Miller JG, Mac Neil S (1997) Gender and cutaneous melanoma. Br J Dermatol 136(5):657–665PubMedGoogle Scholar
  164. Mills SJ, Ashworth JJ, Gilliver SC, Hardman MJ, Ashcroft GS (2005) The sex steroid precursor dhea accelerates cutaneous wound healing via the estrogen receptors. J Invest Dermatol 125(5):1053–1062PubMedGoogle Scholar
  165. Miquel J, Economos AC, Fleming J, Johnson JE Jr (1980) Mitochondrial role in cell aging. Exp Gerontol 15(6):575–591PubMedGoogle Scholar
  166. Mitchell RE (1967) Chronic solar dermatosis: a light and electron microscopic study of the dermis. J Invest Dermatol 48(3):203–220PubMedGoogle Scholar
  167. Monteiro-Riviere NA, Banks YB, Birnbaum LS (1991) Laser Doppler measurements of cutaneous blood flow in ageing mice and rats. Toxicol Lett 57(3):329–338PubMedGoogle Scholar
  168. Moraes AB, Haidar MA, Soares JMJ, Simoes MJ, Baracat EC, Patriarca MT (2009) The effects of topical isoflavones on postmenopausal skin: double-blind and randomized clinical trial of efficacy. Eur J Obstet Gynecol Reprod Biol 146:188–192PubMedGoogle Scholar
  169. Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK, Schnaper HW (1995) Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91(3):755–763PubMedGoogle Scholar
  170. Morin GB (1989) The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes ttaggg repeats. Cell 59(3):521–529PubMedGoogle Scholar
  171. Morris GM, van den Aardweg GJ, Hamlet R, Whitehouse E, Hopewell JW, Franke H, Loeffler M (1990) Age-related changes in the cell kinetics of rat foot epidermis. Cell Tissue Kinet 23(2):113–123PubMedGoogle Scholar
  172. Morrison JH, Brinton RD, Schmidt PJ, Gore AC (2006) Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. J Neurosci 26(41):10332–10348PubMedGoogle Scholar
  173. Mosselman S, Polman J, Dijkema R (1996) Er beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392(1):49–53PubMedGoogle Scholar
  174. Motola DL, Cummins CL, Rottiers V, Sharma KK, Li T, Li Y, Suino-Powell K, Xu HE, Auchus RJ, Antebi A, Mangelsdorf DJ (2006) Identification of ligands for daf-12 that govern dauer formation and reproduction in c. Elegans. Cell 124(6):1209–1223PubMedGoogle Scholar
  175. Mousavi SR, Raaiszadeh M, Aminseresht M, Behjoo S (2010) Evaluating tamoxifen effect in the prevention of hypertrophic scars following surgical incisions. Dermatol Surg 36(5):665–669PubMedGoogle Scholar
  176. Nyman S (1971) Studies on the influence of estradiol and progesterone on granulation tissue. J Periodontal Res Suppl 7:1–24PubMedGoogle Scholar
  177. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (1998) The complete primary structure of human estrogen receptor beta (her beta) and its heterodimerization with er alpha in vivo and in vitro. Biochem Biophys Res Commun 243(1):122–126PubMedGoogle Scholar
  178. Onoe Y, Miyaura C, Ohta H, Nozawa S, Suda T (1997) Expression of estrogen receptor beta in rat bone. Endocrinology 138(10):4509–4512PubMedGoogle Scholar
  179. Owsley C, McGwin G, Scilley K, Meek GC, Dyer A, Seker D (2007) The visual status of older persons residing in nursing homes. Arch Ophthalmol 125(7):925–930PubMedGoogle Scholar
  180. Pickar JH, Macneil T, Ohleth K (2010) Serms: progress and future perspectives. Maturitas 67(2):129–138PubMedGoogle Scholar
  181. Pierard-Franchimont C, Letawe C, Goffin V, Pierard GE (1995) Skin water-holding capacity and transdermal estrogen therapy for menopause: a pilot study. Maturitas 22(2):151–154PubMedGoogle Scholar
  182. Pillai S, Oresajo C, Hayward J (2005) Ultraviolet radiation and skin aging: roles of reactive oxygen species, inflammation and protease activation, and strategies for prevention of inflammation-induced matrix degradation—a review. Int J Cosmet Sci 27(1):17–34PubMedGoogle Scholar
  183. Pinto RE, Bartley W (1968) Changes in glutathione reductase and glutathione peroxidase activities in rat liver related to age and sex. Biochem J 109(3):34PPubMedGoogle Scholar
  184. Pinto RE, Bartley W (1969) The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates. Biochem J 112(1):109–115PubMedGoogle Scholar
  185. Pletcher SD, Macdonald SJ, Marguerie R, Certa U, Stearns SC, Goldstein DB, Partridge L (2002) Genome-wide transcript profiles in aging and calorically restricted drosophila melanogaster. Curr Biol 12(9):712–723PubMedGoogle Scholar
  186. Pochi PE, Strauss JS, Downing DT (1979) Age-related changes in sebaceous gland activity. J Invest Dermatol 73(1):108–111PubMedGoogle Scholar
  187. Punnonen R (1971) On the effect of castration and peroral estrogen therapy on the skin. Acta Obstet Gynecol Scand 9(Suppl 9):32PubMedGoogle Scholar
  188. Punnonen R, Vaajalahti P, Teisala K (1987) Local oestriol treatment improves the structure of elastic fibers in the skin of postmenopausal women. Ann Chir Gynaecol Suppl 202:39–41PubMedGoogle Scholar
  189. Qiu Y, Waters CE, Lewis AE, Langman MJ, Eggo MC (2002) Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J Endocrinol 174(3):369–377PubMedGoogle Scholar
  190. Rajabi MA, Rajabi F (2007) The effect of estrogen on wound healing in rats. Pak J Med Sci 23(3):349–352Google Scholar
  191. Ramsey JJ, Colman RJ, Binkley NC, Christensen JD, Gresl TA, Kemnitz JW, Weindruch R (2000) Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp Gerontol 35(9–10):1131–1149PubMedGoogle Scholar
  192. Reed GA, Tawfik O, Casparian JM (2005) Immunohistochemical analysis of steroid hormone receptors and structural proteins in skin: effects of aging and hormone status. J Appl Res 5(2):371–377Google Scholar
  193. Rezzi S, Martin FP, Shanmuganayagam D, Colman RJ, Nicholson JK, Weindruch R (2009) Metabolic shifts due to long-term caloric restriction revealed in nonhuman primates. Exp Gerontol 44(5):356–362PubMedGoogle Scholar
  194. Richard S, Querleux B, Bittoun J, Jolivet O, Idy-Peretti I, de Lacharriere O, Leveque JL (1993) Characterization of the skin in vivo by high resolution magnetic resonance imaging: water behavior and age-related effects. J Invest Dermatol 100(5):705–709PubMedGoogle Scholar
  195. Sadoun E, Reed MJ (2003) Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J Histochem Cytochem 51(9):1119–1130PubMedGoogle Scholar
  196. Sadowska-Krowicka H, Mannick EE, Oliver PD, Sandoval M, Zhang XJ, Eloby-Childess S, Clark DA, Miller MJ (1998) Genistein and gut inflammation: role of nitric oxide. Proc Soc Exp Biol Med 217(3):351–357PubMedGoogle Scholar
  197. Sakuraoka K, Tajima S, Seyama Y, Teramoto K, Ishibashi M (1996) Analysis of connective tissue macromolecular components in ishibashi rat skin: role of collagen and elastin in cutaneous aging. J Dermatol Sci 12(3):232–237PubMedGoogle Scholar
  198. Sandblom P, Petersen P, Muren A (1953) Determination of the tensile strength of the healing wound as a clinical test. Acta Chir Scand 105(1–4):252–257PubMedGoogle Scholar
  199. Sanz A, Hiona A, Kujoth GC, Seo AY, Hofer T, Kouwenhoven E, Kalani R, Prolla TA, Barja G, Leeuwenburgh C (2007) Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice. Exp Gerontol 42(3):173–182PubMedGoogle Scholar
  200. Sastre J, Pallardo FV, Vina J (2000) Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49(5):427–435PubMedGoogle Scholar
  201. Sato R, Maesawa C, Fujisawa K, Wada K, Oikawa K, Takikawa Y, Suzuki K, Oikawa H, Ishikawa K, Masuda T (2004) Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis. Gut 53(7):1001–1009PubMedGoogle Scholar
  202. Savvas M, Bishop J, Laurent G, Watson N, Studd J (1993) Type iii collagen content in the skin of postmenopausal women receiving oestradiol and testosterone implants. Br J Obstet Gynaecol 100(2):154–156PubMedGoogle Scholar
  203. Sawaya ME, Penneys NS (1992) Immunohistochemical distribution of aromatase and 3b-hydroxysteroid dehydrogenase in human hair follicle and sebaceous gland. J Cutan Pathol 19(4):309–314PubMedGoogle Scholar
  204. Schmidt JB, Binder M, Macheiner W, Kainz C, Gitsch G, Bieglmayer C (1994) Treatment of skin ageing symptoms in perimenopausal females with estrogen compounds. A pilot study. Maturitas 20(1):25–30PubMedGoogle Scholar
  205. Schmidt JB, Binder M, Demschik G, Bieglmayer C, Reiner A (1996) Treatment of skin aging with topical estrogens. Int J Dermatol 35(9):669–674PubMedGoogle Scholar
  206. Schneider EL, Mitsui Y (1976) The relationship between in vitro cellular aging and in vivo human age. Proc Natl Acad Sci USA 73(10):3584–3588PubMedGoogle Scholar
  207. Schroeder P, Gremmel T, Berneburg M, Krutmann J (2008) Partial depletion of mitochondrial DNA from human skin fibroblasts induces a gene expression profile reminiscent of photoaged skin. J Invest Dermatol 128(9):2297–2303PubMedGoogle Scholar
  208. Seibel J, Molzberger AF, Hertrampf T, Laudenbach-Leschowski U, Diel P (2009) Oral treatment with genistein reduces the expression of molecular and biochemical markers of inflammation in a rat model of chronic tnbs-induced colitis. Eur J Nutr 48(4):213–220PubMedGoogle Scholar
  209. Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22(3):807–818PubMedGoogle Scholar
  210. Shaw TJ, Martin P (2009) Wound repair at a glance. J Cell Sci 122(Pt 18):3209–3213PubMedGoogle Scholar
  211. Shuster S, Black MM, McVitie E (1975) The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 93(6):639–643PubMedGoogle Scholar
  212. Shyong EQ, Lu Y, Lazinsky A, Saladi RN, Phelps RG, Austin LM, Lebwohl M, Wei H (2002) Effects of the isoflavone 4′,5,7-trihydroxyisoflavone (genistein) on psoralen plus ultraviolet a radiation (puva)-induced photodamage. Carcinogenesis 23(2):317–321PubMedGoogle Scholar
  213. Siesky BA, Harris A, Patel C, Klaas CL, Harris M, McCranor LJ, Lauer J, Kaplan B (2008) Comparison of visual function and ocular hemodynamics between pre- and post-menopausal women. Eur J Ophthalmol 18(2):320–323PubMedGoogle Scholar
  214. Simon AF, Shih C, Mack A, Benzer S (2003) Steroid control of longevity in drosophila melanogaster. Science 299(5611):1407–1410PubMedGoogle Scholar
  215. Simonen O, Mikkola T (1991) Senile osteoporosis and femoral neck fractures in long-stay institutions. Calcif Tissue Int 49 Suppl:S78–S79PubMedGoogle Scholar
  216. Simpkins JW, Yang SH, Wen Y, Singh M (2005) Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies. Cell Mol Life Sci 62(3):271–280PubMedGoogle Scholar
  217. Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM, Graham-Lorence S, Sun T, Fisher CR, Qin K, Mendelson CR (1997) Aromatase expression in health and disease. Recent Prog Horm Res 52:185–213 (discussion 213–184)PubMedGoogle Scholar
  218. Smith QT, Allison DJ (1966) Changes of collagen content in skin, femur and uterus of 17-beta-estradiol benzoate-treated rats. Endocrinology 79(3):486–492PubMedGoogle Scholar
  219. Sobel H, Lee KD, Hewlett MJ (1965) Effect of estrogen on acid glycosaminoglycans in skin of mice. Biochim Biophys Acta 101(2):225–229PubMedGoogle Scholar
  220. Son ED, Lee JY, Lee S, Kim MS, Lee BG, Chang IS, Chung JH (2005) Topical application of 17beta-estradiol increases extracellular matrix protein synthesis by stimulating tgf-beta signaling in aged human skin in vivo. J Invest Dermatol 124(6):1149–1161PubMedGoogle Scholar
  221. Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R (1987) Factors influencing the age at natural menopause. J Chronic Dis 40(11):995–1002PubMedGoogle Scholar
  222. Stanulis-Praeger BM, Gilchrest BA (1986) Growth factor responsiveness declines during adulthood for human skin-derived cells. Mech Ageing Dev 35(2):185–198PubMedGoogle Scholar
  223. Stanulis-Praeger BM, Gilchrest BA (1989) Effect of donor age and prior sun exposure on growth inhibition of cultured human dermal fibroblasts by all trans-retinoic acid. J Cell Physiol 139(1):116–124PubMedGoogle Scholar
  224. Stevenson S, Sharpe DT, Thornton MJ (2009) Effects of oestrogen agonists on human dermal fibroblasts in an in vitro wounding assay. Exp Dermatol 18(11):988–990PubMedGoogle Scholar
  225. Sthoeger ZM, Zinger H, Mozes E (2003) Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (nzbxnzw)f1 female mice are associated with specific reduction of igg3 autoantibodies. Ann Rheum Dis 62(4):341–346PubMedGoogle Scholar
  226. Stindl R (2004) Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy. Med Hypotheses 62(1):151–154PubMedGoogle Scholar
  227. Sugimoto M, Yamashita R, Ueda M (2006) Telomere length of the skin in association with chronological aging and photoaging. J Dermatol Sci 43(1):43–47PubMedGoogle Scholar
  228. Sumino H, Ichikawa S, Abe M, Endo Y, Ishikawa O, Kurabayashi M (2004) Effects of aging, menopause, and hormone replacement therapy on forearm skin elasticity in women. J Am Geriatr Soc 52(6):945–949PubMedGoogle Scholar
  229. Sumino H, Ichikawa S, Kasama S, Takahashi T, Kumakura H, Takayama Y, Kanda T, Murakami M, Kurabayashi M (2009) Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women. Maturitas 62(1):53–57PubMedGoogle Scholar
  230. Surazynski A, Jarzabek K, Haczynski J, Laudanski P, Palka J, Wolczynski S (2003) Differential effects of estradiol and raloxifene on collagen biosynthesis in cultured human skin fibroblasts. Int J Mol Med 12(5):803–809PubMedGoogle Scholar
  231. Suthers K, Kim JK, Crimmins E (2003) Life expectancy with cognitive impairment in the older population of the United States. J Gerontol B Psychol Sci Soc Sci 58(3):S179–S186PubMedGoogle Scholar
  232. Taguchi A, Wartschow LM, White MF (2007) Brain irs2 signaling coordinates life span and nutrient homeostasis. Science 317(5836):369–372PubMedGoogle Scholar
  233. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292(5514):107–110PubMedGoogle Scholar
  234. Thiboutot D, Martin P, Volikos L, Gilliland K (1998) Oxidative activity of the type 2 isozyme of 17beta-hydroxysteroid dehydrogenase (17beta-hsd) predominates in human sebaceous glands. J Invest Dermatol 111(3):390–395PubMedGoogle Scholar
  235. Thiboutot D, Bayne E, Thorne J, Gilliland K, Flanagan J, Shao Q, Light J, Helm K (2000) Immunolocalization of 5alpha-reductase isozymes in acne lesions and normal skin. Arch Dermatol 136(9):1125–1129PubMedGoogle Scholar
  236. Thiers BH, Maize JC, Spicer SS, Cantor AB (1984) The effect of aging and chronic sun exposure on human langerhans cell populations. J Invest Dermatol 82(3):223–226PubMedGoogle Scholar
  237. Thomas JR (2005) Effects of age and diet on rat skin histology. Laryngoscope 115(3):405–411PubMedGoogle Scholar
  238. Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O’Driscoll J, Messenger AG (2003a) The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit. J Investig Dermatol Symp Proc 8(1):100–103PubMedGoogle Scholar
  239. Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O’Driscoll J, Messenger AG (2003b) Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin. Exp Dermatol 12(2):181–190PubMedGoogle Scholar
  240. Tian DS, Liu JL, Xie MJ, Zhan Y, Qu WS, Yu ZY, Tang ZP, Pan DJ, Wang W (2009) Tamoxifen attenuates inflammatory-mediated damage and improves functional outcome after spinal cord injury in rats. J Neurochem 109(6):1658–1667PubMedGoogle Scholar
  241. Tiganescu A, Walker EA, Hardy RS, Mayes AE, Stewart PM (2011) Localization, age- and site-dependent expression, and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in skin. J Invest Dermatol 131(1):30–36PubMedGoogle Scholar
  242. Toutain CE, Brouchet L, Raymond-Letron I, Vicendo P, Berges H, Favre J, Fouque MJ, Krust A, Schmitt AM, Chambon P, Gourdy P, Arnal JF, Lenfant F (2009) Prevention of skin flap necrosis by estradiol involves reperfusion of a protected vascular network. Circ Res 104(2):245–254 (212p following 254)PubMedGoogle Scholar
  243. Tresguerres JA, Kireev R, Tresguerres AF, Borras C, Vara E, Ariznavarreta C (2008) Molecular mechanisms involved in the hormonal prevention of aging in the rat. J Steroid Biochem Mol Biol 108(3–5):318–326PubMedGoogle Scholar
  244. Trichopoulos D, MacMahon B, Cole P (1972) Menopause and breast cancer risk. J Natl Cancer Inst 48(3):605–613PubMedGoogle Scholar
  245. Tsoureli-Nikita E, Watson RE, Griffiths CE (2006) Photoageing: the darker side of the sun. Photochem Photobiol Sci 5(2):160–164PubMedGoogle Scholar
  246. Tsukahara K, Moriwaki S, Ohuchi A, Fujimura T, Takema Y (2001) Ovariectomy accelerates photoaging of rat skin. Photochem Photobiol 73(5):525–531PubMedGoogle Scholar
  247. Tsukahara K, Nakagawa H, Moriwaki S, Kakuo S, Ohuchi A, Takema Y, Imokawa G (2004) Ovariectomy is sufficient to accelerate spontaneous skin ageing and to stimulate ultraviolet irradiation-induced photoageing of murine skin. Br J Dermatol 151(5):984–994PubMedGoogle Scholar
  248. Varani J, Spearman D, Perone P, Fligiel SE, Datta SC, Wang ZQ, Shao Y, Kang S, Fisher GJ, Voorhees JJ (2001) Inhibition of type i procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. Am J Pathol 158(3):931–942PubMedGoogle Scholar
  249. Varila E, Rantala I, Oikarinen A, Risteli J, Reunala T, Oksanen H, Punnonen R (1995) The effect of topical oestradiol on skin collagen of postmenopausal women. Br J Obstet Gynaecol 102(12):985–989PubMedGoogle Scholar
  250. Verdier-Sevrain S, Yaar M, Cantatore J, Traish A, Gilchrest BA (2004) Estradiol induces proliferation of keratinocytes via a receptor mediated mechanism. FASEB J 18(11):1252–1254PubMedGoogle Scholar
  251. Vina J, Borras C, Gambini J, Sastre J, Pallardo FV (2005) Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds. FEBS Lett 579(12):2541–2545PubMedGoogle Scholar
  252. Vukelic S, Stojadinovic O, Pastar I, Rabach M, Krzyzanowska A, Lebrun E, Davis SC, Resnik S, Brem H, Tomic-Canic M (2011) Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem. doi: 10.1074/jbc.M110.188268
  253. Waetjen LE, Ye J, Feng WY, Johnson WO, Greendale GA, Sampselle CM, Sternfield B, Harlow SD, Gold EB (2009) Association between menopausal transition stages and developing urinary incontinence. Obstet Gynecol 114(5):989–998PubMedGoogle Scholar
  254. Walter P, Green S, Greene G, Krust A, Bornert JM, Jeltsch JM, Staub A, Jensen E, Scrace G, Waterfield M et al (1985) Cloning of the human estrogen receptor cdna. Proc Natl Acad Sci USA 82(23):7889–7893PubMedGoogle Scholar
  255. Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55(11):2284–2292PubMedGoogle Scholar
  256. Wang YN, Wu W, Chen HC, Fang H (2010) Genistein protects against uvb-induced senescence-like characteristics in human dermal fibroblast by p66shc down-regulation. J Dermatol Sci 58(1):19–27PubMedGoogle Scholar
  257. Weinstein BE, Ventry IM (1982) Hearing impairment and social isolation in the elderly. J Speech Hear Res 25(4):593–599PubMedGoogle Scholar
  258. Weinstock MA (1994) Epidemiologic investigation of nonmelanoma skin cancer mortality: the Rhode Island follow-back study. J Invest Dermatol 102(6):6S–9SPubMedGoogle Scholar
  259. Wich SA, Utami-Atmoko SS, Setia TM, Rijksen HD, Schurmann C, van Hooff JA, van Schaik CP (2004) Life history of wild sumatran orangutans (pongo abelii). J Hum Evol 47(6):385–398PubMedGoogle Scholar
  260. Widyarini S, Spinks N, Husband AJ, Reeve VE (2001) Isoflavonoid compounds from red clover (trifolium pratense) protect from inflammation and immune suppression induced by UV radiation. Photochem Photobiol 74(3):465–470PubMedGoogle Scholar
  261. Williams ME, Pannill FC III (1982) Urinary incontinence in the elderly: physiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 97(6):895–907PubMedGoogle Scholar
  262. Yamawaki TM, Berman JR, Suchanek-Kavipurapu M, McCormick M, Maria Gaglia M, Lee SJ, Kenyon C (2010) The somatic reproductive tissues of c. Elegans promote longevity through steroid hormone signaling. PLoS Biol 8(8):e1000468PubMedGoogle Scholar
  263. Yancik R, Ganz PA, Varricchio CG, Conley B (2001) Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol 19(4):1147–1151PubMedGoogle Scholar
  264. Yang JZ, O’Flatharta C, Harvey BJ, Thomas W (2008) Membrane eralpha-dependent activation of pkcalpha in endometrial cancer cells by estradiol. Steroids 73(11):1110–1122PubMedGoogle Scholar
  265. Zou K, Ing NH (1998) Oestradiol up-regulates oestrogen receptor, cyclophilin, and glyceraldehyde phosphate dehydrogenase mRNA concentrations in endometrium, but down-regulates them in liver. J Steroid Biochem Mol Biol 64(5–6):231–237PubMedGoogle Scholar
  266. Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, Scherbaum WA, Orfanos CE, McCann SM, Bornstein SR (2002) Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci USA 99(10):7148–7153PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Faculty of Life SciencesThe University of ManchesterManchesterUK

Personalised recommendations