Iron Chelators & HIF-1α: A New Frontier for Skin Rejuvenation

  • Andrea Pagani
  • Matthias M. Aitzetmüller
  • Dominik Duscher


Advanced age brings changes to all components of the integumentary system with consequent signs of deterioration on epidermis, dermis, and hypodermis. During the aging process, skin gets progressively thinner and the blood capillaries of the dermis become sparse and more fragile, resulting in wrinkles and a paler, translucent appearance. Similar to chronic wounds, skin-aging is characterized by dysfunction of key cellular regulatory pathways. Recent evidence suggests that the same mechanisms, which hinder the physiologic healing response in chronic wounds, are the reason for impaired tissue homeostasis in aged skin. The Hypoxia Inducible Factor 1 alpha (HIF-1α) pathway represents one key-mechanism in both conditions. The HIF-1 pathway is significantly involved in tissue homeostasis and neovascularization. In this chapter, we describe the promising possibilities of a therapeutic modulation of hypoxia inducible signaling pathways by repurposing iron chelators.


Skin rejuvenation HIF1 signaling Hypoxia inducible factor Skin regeneration 


  1. 1.
    Montagna W. The evolution of human skin (?). J Hum Evol. 1985;14(1):3–22.CrossRefGoogle Scholar
  2. 2.
    Tissot FS, Boulter E, Estrach S, Feral CC. The body’s tailored suit: skin as a mechanical interface. Eur J Cell Biol. 2016;95(11):475–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Gniadecka M, Nielsen OF, Wessel S, Heidenheim M, Christensen DH, Wulf HC. Water and protein structure in photoaged and chronically aged skin. J Invest Dermatol. 1998;111(6):1129–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Triassi M, Petrella M, Villari P, Pavia M. Trends and some characteristics of female genital neoplasm mortality in the Campania Region. Ann Ig. 1990;2(4):251–62.PubMedGoogle Scholar
  5. 5.
    Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet. 2013;132(12):1323–38.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Sinclair DA, Guarente L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell. 1997;91(7):1033–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Hershey D, Lee WE. Entropy, aging and death. Syst Res Behav Sci. 1987;4(4):269–81.Google Scholar
  8. 8.
    DiLoreto R, Murphy CT. The cell biology of aging. Mol Biol Cell. 2015;26(25):4524–31.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol. 2008;144(5):666–72.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Fries JF. Aging, natural death, and the compression of morbidity. Bull World Health Organ. 2002;80(3):245–50.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Berneburg M, Plettenberg H, Krutmann J. Photoaging of human skin. Photodermatol Photoimmunol Photomed. 2000;16(6):239–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Uitto J, Bernstein EF. Molecular mechanisms of cutaneous aging: connective tissue alterations in the dermis. J Invest Dermatol Symp Proc. 1998;3(1):41–4. ElsevierPubMedCrossRefGoogle Scholar
  13. 13.
    Kosmadaki M, Gilchrest B. The role of telomeres in skin aging/photoaging. Micron. 2004;35(3):155–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Masaki H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci. 2010;58(2):85–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Investig Dermatol. 2006;126(12):2565–75.PubMedCrossRefGoogle Scholar
  16. 16.
    Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J, et al. Telomere length as an indicator of biological aging. Hypertension. 2001;37(2):381–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992;225(4):951–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Boccardi V, Paolisso G, Mecocci P. Nutrition and lifestyle in healthy aging: the telomerase challenge. Aging (Albany NY). 2016;8(1):12.CrossRefGoogle Scholar
  19. 19.
    Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138(11):1462–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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(2):415–24.PubMedCrossRefGoogle Scholar
  22. 22.
    Quan T, Fisher GJ. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontology. 2015;61(5):427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Heng JK, Aw DC, Tan KB. Solar elastosis in its papular form: uncommon, mistakable. Case Rep Dermatol. 2014;6(1):124–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rando TA. Stem cells, ageing and the quest for immortality. Nature. 2006;441(7097):1080–6.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Fujiwara T, Dohi T, Maan ZN, Rustad KC, Kwon SH, Padmanabhan J, et al. Age-associated intracellular superoxide dismutase deficiency potentiates dermal fibroblast dysfunction during wound healing. Exp Dermatol. 2019;28(4):485–92.PubMedCrossRefGoogle Scholar
  26. 26.
    Fujiwara T, Duscher D, Rustad KC, Kosaraju R, Rodrigues M, Whittam AJ, et al. Extracellular superoxide dismutase deficiency impairs wound healing in advanced age by reducing neovascularization and fibroblast function. Exp Dermatol. 2016;25(3):206–11.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kaisers W, Boukamp P, Stark H-J, Schwender H, Tigges J, Krutmann J, et al. Age, gender and UV-exposition related effects on gene expression in in vivo aged short term cultivated human dermal fibroblasts. PLoS One. 2017;12(5):e0175657.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science (New York, NY). 2015;348(6232):aaa2151.CrossRefGoogle Scholar
  29. 29.
    Huertas ACM, Schmelzer CE, Hoehenwarter W, Heyroth F, Heinz A. Molecular-level insights into aging processes of skin elastin. Biochimie. 2016;128:163–73.CrossRefGoogle Scholar
  30. 30.
    Qin Z, Balimunkwe R, Quan T. Age-related reduction of dermal fibroblast size up-regulates multiple matrix metalloproteinases as observed in aged human skin in vivo. Br J Dermatol. 2017;177(5):1337–48.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Freitas-Rodríguez S, Folgueras AR, López-Otín C. The role of matrix metalloproteinases in aging: tissue remodeling and beyond. Amsterdam: Elsevier; 2017.Google Scholar
  32. 32.
    Rezvani HR, Ali N, Nissen LJ, Harfouche G, De Verneuil H, Taïeb A, et al. HIF-1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Investig Dermatol. 2011;131(9):1793–805.PubMedCrossRefGoogle Scholar
  33. 33.
    Gosain A, DiPietro LA. Aging and wound healing. World J Surg. 2004;28(3):321–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Chang EI, Loh SA, Ceradini DJ, Chang EI, Lin SE, Bastidas N, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation. 2007;116(24):2818–29.PubMedCrossRefGoogle Scholar
  35. 35.
    Duscher D, Januszyk M, Maan ZN, Whittam AJ, Hu MS, Walmsley GG, et al. Comparison of the iron chelator deferoxamine and the hydroxylase inhibitor DMOG in aged and diabetic wound healing. Plast Reconstr Surg. 2015;116:2818–29.Google Scholar
  36. 36.
    Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M, et al. Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci U S A. 2015;112(1):94–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Rezvani HR, Ali N, Nissen LJ, Harfouche G, de Verneuil H, Taieb A, et al. HIF-1alpha in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Invest Dermatol. 2011;131(9):1793–805.PubMedCrossRefGoogle Scholar
  38. 38.
    Rezvani HR, Ali N, Serrano-Sanchez M, Dubus P, Varon C, Ged C, et al. Loss of epidermal hypoxia-inducible factor-1alpha accelerates epidermal aging and affects re-epithelialization in human and mouse. J Cell Sci. 2011;124(Pt 24):4172–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Loh SA, Chang EI, Galvez MG, Thangarajah H, El-ftesi S, Vial IN, et al. SDF-1 alpha expression during wound healing in the aged is HIF dependent. Plast Reconstr Surg. 2009;123(2 Suppl):65S–75S.PubMedCrossRefGoogle Scholar
  40. 40.
    Gould L, Abadir P, Brem H, Carter M, Conner-Kerr T, Davidson J, et al. Chronic wound repair and healing in older adults: current status and future research. J Am Geriatr Soc. 2015;63(3):427–38.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858–64.CrossRefGoogle Scholar
  42. 42.
    Sarkar K, Fox-Talbot K, Steenbergen C, Bosch-Marce M, Semenza GL. Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci U S A. 2009;106(44):18769–74.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Walmsley GG, Maan ZN, Wong VW, Duscher D, Hu MS, Zielins ER, et al. Scarless wound healing: chasing the holy grail. Plast Reconstr Surg. 2015;135(3):907–17.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Duscher D, Maan ZN, Whittam AJ, Sorkin M, Hu MS, Walmsley GG, et al. Fibroblast-specific deletion of hypoxia inducible factor-1 critically impairs murine cutaneous neovascularization and wound healing. Plast Reconstr Surg. 2015;136(5):1004–13.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, et al. The role of hypoxia-inducible factor in wound healing. Adv Wound Care. 2014;3(5):390–9.CrossRefGoogle Scholar
  46. 46.
    Paik KJ, Maan ZN, Zielins ER, Duscher D, Whittam AJ, Morrison SD, et al. Short hairpin RNA silencing of PHD-2 improves neovascularization and functional outcomes in diabetic wounds and ischemic limbs. PLoS One. 2016;11(3):e0150927.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Maxwell PH, Wiesener MS, Chang G-W, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.CrossRefGoogle Scholar
  48. 48.
    Yu F, White SB, Zhao Q, Lee FS. Dynamic, site-specific interaction of hypoxia-inducible factor-1α with the von Hippel-Lindau tumor suppressor protein. Cancer Res. 2001;61(10):4136–42.PubMedGoogle Scholar
  49. 49.
    Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J. 2001;20(18):5197–206.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Ebert BL, Bunn HF. Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and p300/CREB binding protein. Mol Cell Biol. 1998;18(7):4089–96.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15(20):2675–86.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science. 2002;295(5556):858–61.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Bedogni B, Welford SM, Cassarino DS, Nickoloff BJ, Giaccia AJ, Powell MB. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell. 2005;8(6):443–54.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Rosenberger C, Solovan C, Rosenberger AD, Jinping L, Treudler R, Frei U, et al. Upregulation of hypoxia-inducible factors in normal and psoriatic skin. J Invest Dermatol. 2007;127(10):2445–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004;95(1):109–16.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, et al. Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol. 2008;217(2):319–27.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Cho YS, Bae JM, Chun YS, Chung JH, Jeon YK, Kim IS, et al. HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1). Biochim Biophys Acta. 2008;1783(2):323–33.PubMedCrossRefGoogle Scholar
  59. 59.
    Michaylira CZ, Nakagawa H. Hypoxic microenvironment as a cradle for melanoma development and progression. Cancer Biol Ther. 2006;5(5):476–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology. 2009;24(2):97–106.PubMedCrossRefGoogle Scholar
  61. 61.
    Biswas S, Roy S, Banerjee J, Hussain SR, Khanna S, Meenakshisundaram G, et al. Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds. Proc Natl Acad Sci U S A. 2010;107(15):6976–81.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000;60(21):6189–95.PubMedGoogle Scholar
  63. 63.
    Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Elson DA, Thurston G, Huang LE, Ginzinger DG, McDonald DM, Johnson RS, et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev. 2001;15(19):2520–32.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Kim KS, Rajagopal V, Gonsalves C, Johnson C, Kalra VK. A novel role of hypoxia-inducible factor in cobalt chloride- and hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. J Immunol. 2006;177(10):7211–24.PubMedCrossRefGoogle Scholar
  66. 66.
    Fitsialos G, Bourget I, Augier S, Ginouves A, Rezzonico R, Odorisio T, et al. HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration. J Cell Sci. 2008;121(Pt 18):2992–3001.CrossRefGoogle Scholar
  67. 67.
    Ryan MC, Christiano AM, Engvall E, Wewer UM, Miner JH, Sanes JR, et al. The functions of laminins: lessons from in vivo studies. Matrix Biol. 1996;15(6):369–81.PubMedCrossRefGoogle Scholar
  68. 68.
    Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 2002;21(15):3919–26.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Rezvani HR, Dedieu S, North S, Belloc F, Rossignol R, Letellier T, et al. Hypoxia-inducible factor-1alpha, a key factor in the keratinocyte response to UVB exposure. J Biol Chem. 2007;282(22):16413–22.PubMedCrossRefGoogle Scholar
  70. 70.
    Duscher D, Januszyk M, Maan ZN, Whittam AJ, Hu MS, Walmsley GG, et al. Comparison of the hydroxylase inhibitor dimethyloxalylglycine and the iron chelator deferoxamine in diabetic and aged wound healing. Plastic Reconstr Surg. 2017;139(3):695e–706e.CrossRefGoogle Scholar
  71. 71.
    Pagani A, Aitzetmüller MM, Brett EA, König V, Wenny R, Thor D, et al. Skin Rejuvenation through HIF-1alpha modulation. Plast Reconstr Surg. 2018;141(4):600e–7e.PubMedCrossRefGoogle Scholar
  72. 72.
    Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343–54.PubMedCrossRefGoogle Scholar
  73. 73.
    Peet D, Linke S. Regulation of HIF: asparaginyl hydroxylation. Novartis Found Symp. 2006;272:37–49. discussion -53, 131–40Google Scholar
  74. 74.
    Kuo KH, Mrkobrada M. A systematic review and meta-analysis of deferiprone monotherapy and in combination with deferoxamine for reduction of iron overload in chronically transfused patients with beta-thalassemia. Hemoglobin. 2014;38(6):409–21.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Moayedi Esfahani BA, Reisi N, Mirmoghtadaei M. Evaluating the safety and efficacy of silymarin in beta-thalassemia patients: a review. Hemoglobin. 2015;39(2):75–80.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Uttam Singh T, et al. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Temiz G, Sirinoglu H, Yesiloglu N, Filinte D, Kacmaz C. Effects of deferoxamine on fat graft survival. Facial Plastic Surg. 2016;32(4):438–43.CrossRefGoogle Scholar
  78. 78.
    Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood. 1993;82(12):3610–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Origa R, Bina P, Agus A, Crobu G, Defraia E, Dessì C, et al. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica. 2005;90(10):1309–14.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Andrea Pagani
    • 1
  • Matthias M. Aitzetmüller
    • 1
    • 2
  • Dominik Duscher
    • 3
  1. 1.Department of Plastic and Hand SurgeryKlinikum rechts der Isar, Technical University of MunichMunichGermany
  2. 2.Section of Plastic and Reconstructive Surgery, Department of Trauma, Hand and Reconstructive SurgeryWestfaelische Wilhelms, University of MuensterMuensterGermany
  3. 3.Department for Plastic Surgery and Hand Surgery, Division of Experimental Plastic SurgeryTechnical University of MunichMunichGermany

Personalised recommendations