Advertisement

Hormonal Regulation and Systemic Signals of Skin Aging

  • Gregory W. CharvilleEmail author
  • Anne Lynn S. Chang

Abstract

Tissues throughout the body share a common systemic environment comprising the multitude of circulating factors transported within the vasculature. These circulating factors, including hormones and nutrients, represent many key determinants of cell growth and function. As animals age, the balance of factors in the systemic circulation shifts and thus alters the cellular environment. The age-dependent changes in the systemic circulation exposes tissues, including skin, to a distinct combination of factors that is reflected by alterations in cell and tissue phenotypes with age. This chapter discusses our current understanding of the changes to the systemic milieu that occur as mammals grow old, the influence of these changes on skin health and disease in aged individuals, and the efforts to therapeutically modulate circulating factors to prevent or reverse aging phenotypes.

Keywords

Stem cells Rejuvenation Wnt Wound-healing Regeneration TGF-β Hormone replacement IGF Cortisol NF-κB 

References

  1. 1.
    Rigopoulos D, Larios G, Katsambas A. Skin signs of systemic diseases. Clin Dermatol. 2011;29:531–40.PubMedCrossRefGoogle Scholar
  2. 2.
    Jackson R. Historical outline of attempts to classify skin diseases. Can Med Assoc J. 1977;116:1165–8.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Liddell K. Hippocrates of Cos (460–377 bc). Clin Exp Dermatol. 2000;25:86–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Branchet MC, Boisnic S, Frances C, Robert AM. Skin thickness changes in normal aging skin. Gerontology. 1990;36:28–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Fenske NA, Lober CW. Structural and functional changes of normal aging skin. J Am Acad Dermatol. 1986;15:571–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Fenske NA, Conard CB. Aging skin. Am Fam Physician. 1988;37:219–30.PubMedGoogle Scholar
  7. 7.
    Kurban RS, Bhawan J. Histologic changes in skin associated with aging. J Dermatol Surg Oncol. 1990;16:908–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317:807–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477:90–4.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Keyes BE, Segal JP, Heller E, Lien WH, Chang CY, Guo X, et al. Nfatc1 orchestrates aging in hair follicle stem cells. Proc Natl Acad Sci U S A. 2013;110:E4950–9.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science. 2007;317:803–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.PubMedCrossRefGoogle Scholar
  14. 14.
    Arking DE, Krebsova A, Macek Sr M, Macek Jr M, Arking A, Mian IS, et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002;99:856–61.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Rando TA. Stem cells, ageing and the quest for immortality. Nature. 2006;441:1080–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Liu L, Rando TA. Manifestations and mechanisms of stem cell aging. J Cell Biol. 2011;193:257–66.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Oshimori N, Fuchs E. Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation. Cell Stem Cell. 2012;10:63–75.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Quan T, Shao Y, He T, Voorhees JJ, Fisher GJ. Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin. J Invest Dermatol. 2010;130:415–24.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Chujo S, Shirasaki F, Kawara S, Inagaki Y, Kinbara T, Inaoki M, et al. Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model. J Cell Physiol. 2005;203:447–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Ashcroft GS, Horan MA, Ferguson MWJ. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Brown RL, Ormsby I, Doetschman TC, Greenhalgh DG. Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen. 1995;3:25–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Le M, Naridze R, Morrison J, Biggs LC, Rhea L, Schutte BC, et al. Transforming growth factor beta 3 is required for excisional wound repair in vivo. PLoS One. 2012;7:e48040.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Martinez-Ferrer M, Afshar-Sherif AR, Uwamariya C, de Crombrugghe B, Davidson JM, Bhowmick NA. Dermal transforming growth factor-? Responsiveness mediates wound contraction and epithelial closure. Am J Pathol. 2010;176:98–107.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Wu L, Siddiqui A, Morris DE, Cox DA, Roth SI, Mustoe TA. Transforming growth factor beta 3 (TGF beta 3) accelerates wound healing without alteration of scar prominence. Histologic and competitive reverse-transcription-polymerase chain reaction studies. Arch Surg. 1997;1960(132):753–60.CrossRefGoogle Scholar
  25. 25.
    Siebert N, Xu W, Grambow E, Zechner D, Vollmar B. Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway. Lab Invest. 2011;91:1753–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Quan T, He T, Kang S, Voorhees JJ, Fisher GJ. Ultraviolet irradiation alters transforming growth factor beta/smad pathway in human skin in vivo. J Invest Dermatol. 2002;119:499–506.PubMedCrossRefGoogle Scholar
  27. 27.
    Quan T, He T, Kang S, Voorhees JJ, Fisher GJ. Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling. Am J Pathol. 2004;165:741–51.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Han K-H, Choi HR, Won CH, Chung JH, Cho KH, Eun HC, et al. Alteration of the TGF-beta/SMAD pathway in intrinsically and UV-induced skin aging. Mech Ageing Dev. 2005;126:560–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen SJ, Yuan W, Mori Y, Levenson A, Trojanowska M, Varga J. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. J Invest Dermatol. 1999;112:49–57.PubMedCrossRefGoogle Scholar
  30. 30.
    Schmid P, Itin P, Cherry G, Bi C, Cox DA. Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol. 1998;152:485–93.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Ghahary A, Shen YJ, Scott PG, Gong Y, Tredget EE. Enhanced expression of mRNA for transforming growth factor-beta, type I and type III procollagen in human post-burn hypertrophic scar tissues. J Lab Clin Med. 1993;122:465–73.PubMedGoogle Scholar
  32. 32.
    Zhang K, Garner W, Cohen L, Rodriguez J, Phan S. Increased types I and III collagen and transforming growth factor-beta 1 mRNA and protein in hypertrophic burn scar. J Invest Dermatol. 1995;104:750–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev. 2007;21:3244–57.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Delfino F, Walker WH. Hormonal regulation of the NF-κB signaling pathway. Mol Cell Endocrinol. 1999;157:1–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Adler AS, Kawahara TLA, Segal E, Chang HY. Reversal of aging by NFkappaB blockade. Cell Cycle. 2008;7:556–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ. Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab. 2001;281:E1137–43.PubMedGoogle Scholar
  37. 37.
    Gupta S, Chiplunkar S, Kim C, Yel L, Gollapudi S. Effect of age on molecular signaling of TNF-alpha-induced apoptosis in human lymphocytes. Mech Ageing Dev. 2003;124:503–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature. 2012;490:355–60.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Komi-Kuramochi A, Kawano M, Oda Y, Asada M, Suzuki M, Oki J, et al. Expression of fibroblast growth factors and their receptors during full-thickness skin wound healing in young and aged mice. J Endocrinol. 2005;186:273–89.PubMedCrossRefGoogle Scholar
  40. 40.
    Lupien SJ, de Leon M, de Santi S, Convit A, Tarshish C, Nair NP, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci. 1998;1:69–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Yen SSC. The biology of menopause. J Reprodin Med Obstet Gynecol. 1977;18:287–96.Google Scholar
  42. 42.
    Hall G, Phillips TJ. Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin. J Am Acad Dermatol. 2005;53:555–68.PubMedCrossRefGoogle Scholar
  43. 43.
    Brincat M, Kabalan S, Studd JW, Moniz CF, de Trafford J, Montgomery J. A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol. 1987;70:840–5.PubMedGoogle Scholar
  44. 44.
    Brincat M, Moniz CJ, Studd JW, Darby A, Magos A, Emburey G, et al. Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol. 1985;92:256–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Sauerbronn AV, Fonseca AM, Bagnoli VR, Saldiva PH, Pinotti JA. The effects of systemic hormonal replacement therapy on the skin of postmenopausal women. Int J Gynaecol Obstet. 2000;68:35–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Castelo-Branco C, Duran M, González-Merlo J. Skin collagen changes related to age and hormone replacement therapy. Maturitas. 1992;15:113–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Maheux R, Naud F, Rioux M, Grenier R, Lemay A, Guy J, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol. 1994;170:642–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Bolognia JL, Braverman IM, Rousseau ME, Sarrel PM. Skin changes in menopause. Maturitas. 1989;11:295–304.PubMedCrossRefGoogle Scholar
  49. 49.
    Varila E, Rantala I, Oikarinen A, Risteli J, Reunala T, Oksanen H, et al. The effect of topical oestradiol on skin collagen of postmenopausal women. Br J Obstet Gynaecol. 1995;102:985–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Punnonen R, Vaajalahti P, Teisala K. Local oestriol treatment improves the structure of elastic fibers in the skin of postmenopausal women. Ann Chir Gynaecol Suppl. 1987;202:39–41.PubMedGoogle Scholar
  51. 51.
    Henry F, Piérard-Franchimont C, Cauwenbergh G, Piérard GE. Age-related changes in facial skin contours and rheology. J Am Geriatr Soc. 1997;45:220–2.PubMedCrossRefGoogle Scholar
  52. 52.
    Piérard GE, Letawe C, Dowlati A, Piérard-Franchimont C. Effect of hormone replacement therapy for menopause on the mechanical properties of skin. J Am Geriatr Soc. 1995;43:662–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Yoon H-S, Lee S-R, Chung JH. Long-term topical oestrogen treatment of sun-exposed facial skin in post-menopausal women does not improve facial wrinkles or skin elasticity, but induces matrix metalloproteinase-1 expression. Acta Derm Venereol. 2014;94:4–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Thornton MJ. Estrogens and aging skin. Dermatoendocrinol. 2013;5:264–70.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol. 1999;155:1137–46.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Margolis DJ, Knauss J, Bilker W. Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet. 2002;359:675–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Ashcroft GS, Dodsworth J, van Boxtel E, Tarnuzzer RW, Horan MA, Schultz GS, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. 1997;3:1209–15.PubMedCrossRefGoogle Scholar
  58. 58.
    Ashcroft GS, Mills SJ, Lei K, Gibbons L, Jeong MJ, Taniguchi M, et al. Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest. 2003;111:1309–18.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872–81.PubMedCrossRefGoogle Scholar
  60. 60.
    Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol. 2004;190:1141–67.PubMedCrossRefGoogle Scholar
  61. 61.
    Surazynski A, Jarzabek K, Haczynski J, Laudanski P, Palka J, Wolczynski S. Differential effects of estradiol and raloxifene on collagen biosynthesis in cultured human skin fibroblasts. Int J Mol Med. 2003;12:803–9.PubMedGoogle Scholar
  62. 62.
    Sumino H, Ichikawa S, Kasama S, Gibbons L, Jeong MJ, Taniguchi M, et al. Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women. Maturitas. 2009;62:53–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Farage MA, Miller KW, Elsner P, Maibach HI. Characteristics of the aging skin. Adv Wound Care. 2013;2:5–10.CrossRefGoogle Scholar
  64. 64.
    Yeap BB. Testosterone and ill-health in aging men. Nat Clin Pract Endocrinol Metab. 2009;5:113–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Sator PG, Schmidt JB, Sator MO, Huber JC, Hönigsmann H. The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas. 2001;39:43–55.PubMedCrossRefGoogle Scholar
  66. 66.
    Wright ET, McGillis TJ, Sobel H. Action of testosterone on the skin of aging male subjects. Dermatology. 1970;140:124–8.CrossRefGoogle Scholar
  67. 67.
    Brawer MK. Testosterone replacement in men with andropause: an overview. Rev Urol. 2004;6:S9–15.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Glaser RL, Dimitrakakis C, Messenger AG. Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study. Br J Dermatol. 2012;166:274–8.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001;116:452–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhuo FL, Xu W, Wang L, Wu Y, Xu ZL, Zhao JY. Androgen receptor gene polymorphisms and risk for androgenetic alopecia: a meta-analysis. Clin Exp Dermatol. 2012;37:104–11.PubMedCrossRefGoogle Scholar
  71. 71.
    Korting HC, Unholzer A, Schäfer-Korting M, Tausch I, Gassmueller J, Nietsch KH. Different skin thinning potential of equipotent medium-strength glucocorticoids. Skin Pharmacol Appl Skin Physiol. 2002;15:85–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes CJ, Breitkreutz D, et al. Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol Cell Biol. 2006;26:2675–87.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Kimura T, Doi K. Dorsal skin reactions of hairless dogs to topical treatment with corticosteroids. Toxicol Pathol. 1999;27:528–35.PubMedCrossRefGoogle Scholar
  74. 74.
    Lavker RM. Structural alterations in exposed and unexposed aged skin. J Invest Dermatol. 1979;73:59–66.PubMedCrossRefGoogle Scholar
  75. 75.
    Lee B, Vouthounis C, Stojadinovic O, Brem H, Im M, Tomic-Canic M. From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol. 2005;345:1083–97.PubMedCrossRefGoogle Scholar
  76. 76.
    Ashcroft GS, Horan MA, Ferguson MW. 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.PubMedCrossRefGoogle Scholar
  77. 77.
    Braverman IM, Fonferko E. Studies in cutaneous aging: I. The elastic fiber network. J Invest Dermatol. 1982;78:434–43.PubMedCrossRefGoogle Scholar
  78. 78.
    Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006;168:1861–8.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Nuutinen P, Riekki R, Parikka M, Salo T, Autio P, Risteli J, et al. Modulation of collagen synthesis and mRNA by continuous and intermittent use of topical hydrocortisone in human skin. Br J Dermatol. 2003;148:39–45.PubMedCrossRefGoogle Scholar
  80. 80.
    Autio P, Oikarinen A, Melkko J, Risteli J, Risteli L. Systemic glucocorticoids decrease the synthesis of type I and type III collagen in human skin in vivo, whereas isotretinoin treatment has little effect. Br J Dermatol. 1994;131:660–3.PubMedCrossRefGoogle Scholar
  81. 81.
    Tiganescu A, Tahrani AA, Morgan SA, Otranto M, Desmoulière A, Abrahams L, et al. 11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest. 2013;123:3051–60.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Tiganescu A, Walker EA, Hardy RS, Mayes AE, Stewart PM. Localization, age- and site-dependent expression, and regulation of 11β-hydroxysteroid dehydrogenase type 1 in skin. J Invest Dermatol. 2011;131:30–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Chang ALS, Bitter Jr PH, Qu K, Lin M, Rapicavoli NA, Chang HY. Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study. J Invest Dermatol. 2013;133:394–402.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Apfeld J, Kenyon C. Cell nonautonomy of C. elegans daf-2 Function in the regulation of diapause and life span. Cell. 1998;95:199–210.PubMedCrossRefGoogle Scholar
  85. 85.
    Kenyon CJ. The genetics of ageing. Nature. 2010;464:504–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105:3438–42.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Vitale G, Brugts MP, Ogliari G, Castaldi D, Fatti LM, Varewijck AJ, et al. Low circulating IGF-I bioactivity is associated with human longevity: findings in centenarians’ offspring. Aging. 2012;4:580–9.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Sugiyama-Nakagiri Y, Naoe A, Ohuchi A, Kitahara T. Serum levels of IGF-1 are related to human skin characteristics including the conspicuousness of facial pores. Int J Cosmet Sci. 2011;33:144–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Chang ALS, Atzmon G, Bergman A, Brugmann S, Atwood SX, Chang HY, et al. Identification of genes promoting skin youthfulness by genome-wide association study. J Invest Dermatol. 2014;134:651–7.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Sadighi Akha AA, Harper JM, Salmon AB, Schroeder BA, Tyra HM, Rutkowski DT, et al. Heightened induction of proapoptotic signals in response to endoplasmic reticulum stress in primary fibroblasts from a mouse model of longevity. J Biol Chem. 2011;286:30344–51.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Le Clerc S, Taing L, Ezzedine K, Latreille J, Delaneau O, Labib T, et al. A genome-wide association study in Caucasian women points out a putative role of the STXBP5L gene in facial photoaging. J Invest Dermatol. 2013;133:929–35.PubMedCrossRefGoogle Scholar
  92. 92.
    Tang X, Wang Y, Li D, Luo J, Liu M. Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin. 2012;33:363–71.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Departments of Dermatology and PathologyStanford University School of MedicineRedwood CityUSA
  2. 2.Department of DermatologyStanford University School of MedicineRedwood CityUSA

Personalised recommendations