Neurotrophins and Skin Aging

  • Mohamed A. Adly
  • Hanan Assaf
  • Mahmoud R. Hussein
Living reference work entry


Cutaneous aging is a complex biological phenomenon that consists of two superimposed components: intrinsic (true aging) and extrinsic (photoaging) aging. Intrinsic aging is largely genetically determined and represents an inevitable change attributable to the passage of time alone. It resembles aging that is seen in most internal organs, and its underlying mechanisms probably involve decreased proliferative capacity, leading to cellular senescence and altered biosynthetic activity of skin-derived cells. Intrinsic aging is manifested primarily by physiologic alterations with subtle but undoubtedly important consequences for both healthy and diseased skin. The morphologic changes of intrinsic aging include smoothing and thinning of the skin with exaggeration of the expression lines. The intrinsic rate of skin aging in any individual is dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light (UV), that is, intrinsic and extrinsic aging are superimposed processes. Extrinsic aging is caused by environmental exposure, primarily to UV. It is observed in the sun-exposed areas (photoaging) and is manifested by the presence of skin wrinkles, pigmented lesions, patchy hypopigmentations, and actinic keratoses. It involves changes in the cellular biosynthetic activity and usually leads to gross disorganization of the dermal matrix. Photodamage, which considerably accelerates the visible aging of skin, also greatly increases the risk of cutaneous neoplasia.


Nerve Growth Factor Human Keratinocytes Epidermal Keratinocytes Human Epidermal Keratinocytes Keratinocyte Proliferation 
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  1. 1.
    Botchkareva NV, Botchkarev VA, Welker P, Airaksinen M, Roth W, Suvanto P, Muller-Rover S, Hadshiew IM, Peters C, Paus R. New roles for glial cell line-derived neurotrophic factor and neurturin: involvement in hair cycle control. Am J Pathol. 2000;156(3):1041–53.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Botchkarev VA, Botchkareva NV, Peters EM, Paus R. Epithelial growth control by neurotrophins: leads and lessons from the hair follicle. Prog Brain Res. 2004;146:493–513.CrossRefPubMedGoogle Scholar
  3. 3.
    Adly MA, Assaf H, Hussein MR. Age-associated decrease of the nerve growth factor protein expression in the human skin: preliminary findings. J Dermatol Sci. 2006;42(3):268–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Teng KK, Hempstead BL. Neurotrophins and their receptors: signaling trios in complex biological systems. Cell Mol Life Sci. 2004;61(1):35–48.CrossRefPubMedGoogle Scholar
  5. 5.
    Segal RA. Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci. 2003;26:299–330.CrossRefPubMedGoogle Scholar
  6. 6.
    Dechant G, Barde YA. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci. 2002;5(11):1131–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Nykjaer A, Willnow TE, Petersen CM. p75NTR – live or let die. Curr Opin Neurobiol. 2005;15(1):49–57.CrossRefPubMedGoogle Scholar
  8. 8.
    Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA. Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem. 2002;277(10):7720–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Peters EM, Hansen MG, Overall RW, Nakamura M, Pertile P, Klapp BF, Arck PC, Paus R. Control of human hair growth by neurotrophins: brain-derived neurotrophic factor inhibits hair shaft elongation, induces catagen, and stimulates follicular transforming growth factor beta2 expression. J Invest Dermatol. 2005;124(4):675–85.CrossRefPubMedGoogle Scholar
  10. 10.
    Peters EM, Hendrix S, Golz G, Klapp BF, Arck PC, Paus R. Nerve growth factor and its precursor differentially regulate hair cycle progression in mice. J Histochem Cytochem. 2006;54(3):275–88.CrossRefPubMedGoogle Scholar
  11. 11.
    Botchkareva NV, Botchkarev VA, Albers KM, Metz M, Paus R. Distinct roles for nerve growth factor and brain-derived neurotrophic factor in controlling the rate of hair follicle morphogenesis. J Invest Dermatol. 2000;114(2):314–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Sariola H. The neurotrophic factors in non-neuronal tissues. Cell Mol Life Sci. 2001;58(8):1061–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Ernfors P, Lee KF, Jaenisch R. Target derived and putative local actions of neurotrophins in the peripheral nervous system. Prog Brain Res. 1994;103:43–54.CrossRefPubMedGoogle Scholar
  14. 14.
    Yaar M, Grossman K, Eller M, Gilchrest BA. Evidence for nerve growth factor-mediated paracrine effects in human epidermis. J Cell Biol. 1991;115(3):821–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Yaar M, Eller MS, DiBenedetto P, Reenstra WR, Zhai S, McQuaid T, Archambault M, Gilchrest BA. The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes. J Clin Invest. 1994;94(4):1550–62.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Botchkarev VA, Metz M, Botchkareva NV, Welker P, Lommatzsch M, Renz H, Paus R. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as “epitheliotrophins” in murine skin. Lab Invest. 1999;79(5):557–72.PubMedGoogle Scholar
  17. 17.
    Adly MA, Assaf HA, Nada EA, Soliman M, Hussein M. Human scalp skin and hair follicles express neurotrophin-3 and its high-affinity receptor tyrosine kinase C, and show hair cycle-dependent alterations in expression. Br J Dermatol. 2005;153(3):514–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Bonini S, Rasi G, Bracci-Laudiero ML, Procoli A, Aloe L. Nerve growth factor: neurotrophin or cytokine? Int Arch Allergy Immunol. 2003;131(2):80–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Aloe L. Nerve growth factor, human skin ulcers and vascularization. Our experience. Prog Brain Res. 2004;146:515–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Marco E, Di Marchisio PC, Bondanza S, Franzi AT, Cancedda R, De Luca M. Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem. 1991;266(32):21718–22.PubMedGoogle Scholar
  21. 21.
    Adly MA, Assaf HA, Nada EA, Soliman M, Hussein M. Expression of nerve growth factor and its high-affinity receptor, tyrosine kinase A proteins, in the human scalp skin. J Cutan Pathol. 2006;33(8):559–68.CrossRefPubMedGoogle Scholar
  22. 22.
    Pincelli C, Sevignani C, Manfredini R, Grande A, Fantini F, Bracci-Laudiero L, Aloe L, Ferrari S, Cossarizza A, Giannetti A. Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes. J Invest Dermatol. 1994;103(1):13–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Stefanato CM, Yaar M, Bhawan J, Phillips TJ, Kosmadaki MG, Botchkarev V, Gilchrest BA. Modulations of nerve growth factor and Bcl-2 in ultraviolet-irradiated human epidermis. J Cutan Pathol. 2003;30(6):351–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Paus R, Luftl M, Czarnetzki BM. Nerve growth factor modulates keratinocyte proliferation in murine skin organ culture. Br J Dermatol. 1994;130(2):174–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Marconi A, Vaschieri C, Zanoli S, Giannetti A, Pincelli C. Nerve growth factor protects human keratinocytes from ultraviolet-B-induced apoptosis. J Invest Dermatol. 1999;113(6):920–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Marconi A, Terracina M, Fila C, Franchi J, Bonte F, Romagnoli G, Maurelli R, Failla CM, Dumas M, Pincelli C. Expression and function of neurotrophins and their receptors in cultured human keratinocytes. J Invest Dermatol. 2003;121(6):1515–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000;10(2):85–90.PubMedGoogle Scholar
  28. 28.
    Pincelli C, Haake AR, Benassi L, Grassilli E, Magnoni C, Ottani D, Polakowska R, Franceschi C, Giannetti A. Autocrine nerve growth factor protects human keratinocytes from apoptosis through its high affinity receptor (TRK): a role for BCL-2. J Invest Dermatol. 1997;109(6):757–64.CrossRefPubMedGoogle Scholar
  29. 29.
    Pincelli C, Yaar M. Nerve growth factor: its significance in cutaneous biology. J Investig Dermatol Symp Proc. 1997;2(1):31–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Wehrli P, Viard I, Bullani R, Tschopp J, French LE. Death receptors in cutaneous biology and disease. J Invest Dermatol. 2000;115(2):141–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Botchkarev VA, Botchkareva NV, Albers KM, Chen LH, Welker P, Paus R. A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression. FASEB J. 2000;14(13):1931–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Adly MA, Assaf HA, Hussein MR. Expression pattern of p75 neurotrophin receptor protein in the human scalp skin and hair follice: hair cycle-dependent expression. J Am Acad Dermatol. 2009;60(1):99–109.CrossRefPubMedGoogle Scholar
  33. 33.
    Krygier S, Djakiew D. The neurotrophin receptor p75NTR is a tumor suppressor in human prostate cancer. Anticancer Res. 2001;21(6A):3749–55.PubMedGoogle Scholar
  34. 34.
    Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169(2):107–14.CrossRefPubMedGoogle Scholar
  35. 35.
    Peacocke M, Yaar M, Mansur CP, Chao MV, Gilchrest BA. Induction of nerve growth factor receptors on cultured human melanocytes. Proc Natl Acad Sci U S A. 1988;85(14):5282–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Marco E, Di Mathor M, Bondanza S, Cutuli N, Marchisio PC, Cancedda R, De Luca M. Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulates their growth by a novel autocrine loop. J Biol Chem. 1993;268(30):22838–46.PubMedGoogle Scholar
  37. 37.
    Zhai S, Yaar M, Doyle SM, Gilchrest BA. Nerve growth factor rescues pigment cells from ultraviolet-induced apoptosis by upregulating BCL-2 levels. Exp Cell Res. 1996;224(2):335–43.CrossRefPubMedGoogle Scholar
  38. 38.
    Alleva E, Petruzzi S, Cirulli F, Aloe L. NGF regulatory role in stress and coping of rodents and humans. Pharmacol Biochem Behav. 1996;54(1):65–72.CrossRefPubMedGoogle Scholar
  39. 39.
    Alberch J, Perez-Navarro E, Arenas E, Marsal J. Involvement of nerve growth factor and its receptor in the regulation of the cholinergic function in aged rats. J Neurochem. 1991;57(5):1483–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Garcia-Suarez O, Germana A, Hannestad J, Perez-Perez M, Esteban I, Naves FJ, Vega JA. Changes in the expression of the nerve growth factor receptors TrkA and p75LNGR in the rat thymus with ageing and increased nerve growth factor plasma levels. Cell Tissue Res. 2000;301(2):225–34.CrossRefPubMedGoogle Scholar
  41. 41.
    Backman C, Rose GM, Hoffer BJ, Henry MA, Bartus RT, Friden P, Granholm AC. Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy. J Neurosci. 1996;16(17):5437–42.PubMedGoogle Scholar
  42. 42.
    Amendola T, Aloe L. Developmental expression of nerve growth factor in the eye of rats affected by inherited retinopathy: correlative aspects with retinal structural degeneration. Arch Ital Biol. 2002;140(2):81–90.PubMedGoogle Scholar
  43. 43.
    Aloe L. Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol. 2004;14(7):395–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mohamed A. Adly
    • 1
  • Hanan Assaf
    • 2
  • Mahmoud R. Hussein
    • 3
  1. 1.Department of ZoologySohag UniversitySohagEgypt
  2. 2.Department of DermatologySaudi German HospitalJeddahSaudi Arabia
  3. 3.Department of PathologyAssir Central Hospital, and Assuit UniversityAssuitEgypt

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