Lab Anim Res.  2011 Mar;27(1):1-8.

Molecular Mechanisms and In Vivo Mouse Models of Skin Aging Associated with Dermal Matrix Alterations

• Hwang KA
• Yi BR
• Choi KC

Abstract

Skin is the most superficial body organ and plays an important role in protecting the body from environmental damage and in forming social relations. With the increase of the aging population in our society, dermatological and cosmetic concerns of skin aging are rapidly increasing. Skin aging is a complex process combined with intrinsic and extrinsic factors. Intrinsic or chronological skin aging results from the passage of time and is influenced by genetic factors. Extrinsic skin aging is mainly determined by UV irradiation, also called photoaging. These two types of aging processes are superimposed on sun-exposed skin, and have a common feature of causing dermal matrix alterations that mostly contribute to the formation of wrinkles, laxity, and fragility of aged skin. The dermal matrix contains extracellular matrix proteins such as collagen, elastin, and proteoglycans that confer the strength and resiliency of skin. Skin aging associated with dermal matrix alterations and atrophy can be caused by cellular senescence of dermal cells like fibroblasts, and decreased synthesis and accelerated degradation of dermal matrix components, especially collagen fibers. Both intrinsic aging and photoaging exert influence during each step of dermal matrix alteration via different mechanisms. Mouse models of skin aging have been extensively developed to elucidate intrinsic aging and photoaging processes, to validate in vitro biochemical data, and to test the effects of pharmacological tools for retarding skin aging because they have the advantages of being genetically similar to humans and are easily available.

Keyword

Intrinsic skin aging; photoaging; dermal matrix alterations; collagen; mouse model

MeSH Terms

Aging
Animals
Atrophy
Cell Aging
Collagen
Cosmetics
Elastin
Extracellular Matrix Proteins
Fibroblasts
Humans
Mice
Proteoglycans
Skin
Skin Aging
Collagen
Cosmetics
Elastin
Extracellular Matrix Proteins
Proteoglycans

Figure

• 

  Figure 1 Common mechanism of type I collagen alteration for intrinsic aging and photoaging in dermal connective tissue. Intrinsic aging induces the down-regulation of transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) in the TGF-β/Smad/CTGF/procollagen axis and leads to decreased synthesis of type I collagen. In photoaging, UV irradiation from the sun generates reactive oxygen species (ROS) which activate growth factor and cytokine receptors on fibroblasts in the skin. Activated receptors stimulate p38 and JNK, members of the MAPK signaling cascade, and c-Fos and c-Jun subsequently combine to form AP-1 which stimulates matrix metalloproteinase (MMP) transcription. Increased MMP transcription accelerates the degradation of collagen which induces dermal matrix alterations. ROS generation and AP-1 formation induced by photoaging can also lead to decreased collagen synthesis by blocking TGF-β type II receptor/Smad signaling. ROS can also be generated from oxidative metabolism and accumulate during the intrinsic aging process.

Reference

1. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA. 1992; 89(21):10114–10118. PMID: 1438199.

2. Bateman A, Chothia C. Fibronectin type III domains in yeast detected by a hidden Markov model. Curr Biol. 1996; 6(12):1544–1547. PMID: 8994808.

3. Baumann L. Skin ageing and its treatment. J Pathol. 2007; 211(2):241–251. PMID: 17200942.

4. Bhattacharyya TK, Thomas JR. Histomorphologic changes in aging skin: observations in the CBA mouse model. Arch Facial Plast Surg. 2004; 6(1):21–25. PMID: 14732640.

5. Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, Bottinger EP. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev. 2000; 14(2):187–197. PMID: 10652273.

6. Black HS. Potential involvement of free radical reactions in ultraviolet light-mediated cutaneous damage. Photochem Photobiol. 1987; 46(2):213–221. PMID: 3628510.

7. Blumenberg M, Tomic-Canic M. Human epidermal keratinocyte: keratinization processes. Exs. 1997; 78:1–29. PMID: 8962489.

8. Boyer B, Kern P, Fourtanier A, Labat-Robert J. Age-dependent variations of the biosyntheses of fibronectin and fibrous collagens in mouse skin. Exp Gerontol. 1991; 26(4):375–383. PMID: 1936196.

9. Brown JD, DiChiara MR, Anderson KR, Gimbrone MA Jr, Topper JN. MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J Biol Chem. 1999; 274(13):8797–8805. PMID: 10085121.

10. Carneiro SC, Cassia Fde F, Pascarelli BM, Souza SO, Ramos-e-Silva M, Filgueira AL, Japiassu MA, Takiya CM. Increase in dermal collagen fibril diameter and elastogenesis with UVB exposure: an optical and ultrastructural study in albino Balb/c mice. Acta Dermatovenerol Croat. 2007; 15(2):65–71. PMID: 17631783.

11. Chung JH, Seo JY, Choi HR, Lee MK, Youn CS, Rhie G, Cho KH, Kim KH, Park KC, Eun HC. Modulation of skin collagen metabolism in aged and photoaged human skin in vivo. J Invest Dermatol. 2001; 117(5):1218–1224. PMID: 11710936.

12. Cristofalo VJ, Pignolo RJ. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev. 1993; 73(3):617–638. PMID: 8332640.

13. Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997; 136(3):729–743. PMID: 9024701.

14. Dimri GP, Hara E, Campisi J. Regulation of two E2F-related genes in presenescent and senescent human fibroblasts. J Biol Chem. 1994; 269(23):16180–16186. PMID: 8206919.

15. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J. 1999; 13(13):1774–1786. PMID: 10506580.

16. Fisher GJ, Datta S, Wang Z, Li XY, Quan T, Chung JH, Kang S, Voorhees JJ. c-Jun-dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoic acid. J Clin Invest. 2000; 106(5):663–670. PMID: 10974019.

17. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees JJ. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002; 138(11):1462–1470. PMID: 12437452.

18. Fornieri C, Quaglino D Jr, Mori G. Correlations between age and rat dermis modifications. Ultrastructural-morphometric evaluations and lysyl oxidase activity. Aging (Milano). 1989; 1(2):127–138. PMID: 2577359.

19. Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010; 123(Pt 24):4195–4200. PMID: 21123617.

20. Furth JJ. The steady-state levels of type I collagen mRNA are reduced in senescent fibroblasts. J Gerontol. 1991; 46(3):B122–B124. PMID: 2030266.

21. Gilchrest BA. Age-associated changes in the skin. J Am Geriatr Soc. 1982; 30(2):139–143. PMID: 7035532.

22. 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):1129–1133. PMID: 9856828.

23. Gore-Hyer E, Shegogue D, Markiewicz M, Lo S, Hazen-Martin D, Greene EL, Grotendorst G, Trojanowska M. TGF-beta and CTGF have overlapping and distinct fibrogenic effects on human renal cells. Am J Physiol Renal Physiol. 2002; 283(4):F707–F716. PMID: 12217862.

24. Grinnell F. Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 2000; 10(9):362–365. PMID: 10932093.

25. Grinnell F. Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol. 2003; 13(5):264–269. PMID: 12742170.

26. Grinnell F, Zhu M, Carlson MA, Abrams JM. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp Cell Res. 1999; 248(2):608–619. PMID: 10222153.

27. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997; 8(3):171–179. PMID: 9462483.

28. Hara E, Uzman JA, Dimri GP, Nehlin JO, Testori A, Campisi J. The helix-loop-helix protein Id-1 and a retinoblastoma protein binding mutant of SV40 T antigen synergize to reactivate DNA synthesis in senescent human fibroblasts. Dev Genet. 1996; 18(2):161–172. PMID: 8934878.

29. Hara E, Yamaguchi T, Nojima H, Ide T, Campisi J, Okayama H, Oda K. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem. 1994; 269(3):2139–2145. PMID: 8294468.

30. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274):458–460. PMID: 2342578.

31. Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem. 2001; 276(14):10594–10601. PMID: 11152469.

32. Ignotz RA, Massague J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986; 261(9):4337–4345. PMID: 3456347.

33. Jenkins G. Molecular mechanisms of skin ageing. Mech Ageing Dev. 2002; 123(7):801–810. PMID: 11869737.

34. Kligman LH. The hairless mouse model for photoaging. Clin Dermatol. 1996; 14(2):183–195. PMID: 9117985.

35. Kligman LH, Gebre M, Alper R, Kefalides NA. Collagen metabolism in ultraviolet irradiated hairless mouse skin and its correlation to histochemical observations. J Invest Dermatol. 1989; 93(2):210–214. PMID: 2474028.

36. Kligman LH, Kligman AM. The nature of photoaging: its prevention and repair. Photodermatol. 1986; 3(4):215–227. PMID: 3534809.

37. Kochevar IE, Moran M, Granstein RD. Experimental photoaging in C3H/HeN, C3H/HeJ, and Balb/c mice: comparison of changes in extracellular matrix components and mast cell numbers. J Invest Dermatol. 1994; 103(6):797–800. PMID: 7798617.

38. Kohen R, Gati I. Skin low molecular weight antioxidants and their role in aging and in oxidative stress. Toxicology. 2000; 148(2-3):149–157. PMID: 10962134.

39. Kosmadaki MG, Gilchrest BA. The role of telomeres in skin aging/photoaging. Micron. 2004; 35(3):155–159. PMID: 15036269.

40. Kyriakides TR, Zhu YH, Smith LT, Bain SD, Yang Z, Lin MT, Danielson KG, Iozzo RV, LaMarca M, McKinney CE, Ginns EI, Bornstein P. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol. 1998; 140(2):419–430. PMID: 9442117.

41. Lee YM, Kim W. Association of human kinesin superfamily protein member 4 with BRCA2-associated factor 35. Biochem J. 2003; 374(Pt 2):497–503. PMID: 12809554.

42. Li GZ, Eller MS, Firoozabadi R, Gilchrest BA. Evidence that exposure of the telomere 3\' overhang sequence induces senescence. Proc Natl Acad Sci USA. 2003; 100(2):527–531. PMID: 12515865.

43. Makrantonaki E, Zouboulis CC. The skin as a mirror of the aging process in the human organism--state of the art and results of the aging research in the German National Genome Research Network 2 (NGFN-2). Exp Gerontol. 2007; 42(9):879–886. PMID: 17689905.

44. Masaki H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci. 2010; 58(2):85–90. PMID: 20399614.

45. Mays PK, McAnulty RJ, Campa JS, Laurent GJ. Age-related changes in collagen synthesis and degradation in rat tissues. Importance of degradation of newly synthesized collagen in regulating collagen production. Biochem J. 1991; 276(Pt 2):307–313. PMID: 2049064.

46. Muscari C, Giaccari A, Giordano E, Clo C, Guarnieri C, Caldarera CM. Role of reactive oxygen species in cardiovascular aging. Mol Cell Biochem. 1996; 160-161:159–166. PMID: 8901470.

47. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006; 69(3):562–573. PMID: 16405877.

48. Nishimori Y, Edwards C, Pearse A, Matsumoto K, Kawai M, Marks R. Degenerative alterations of dermal collagen fiber bundles in photodamaged human skin and UV-irradiated hairless mouse skin: possible effect on decreasing skin mechanical properties and appearance of wrinkles. J Invest Dermatol. 2001; 117(6):1458–1463. PMID: 11886509.

49. Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994; 211(1):90–98. PMID: 8125163.

50. Okamoto O, Fujiwara S. Dermatopontin, a novel player in the biology of the extracellular matrix. Connect Tissue Res. 2006; 47(4):177–189. PMID: 16987749.

51. Oxlund H, Andreassen TT. The roles of hyaluronic acid, collagen and elastin in the mechanical properties of connective tissues. J Anat. 1980; 131(Pt 4):611–620. PMID: 7216901.

52. Pimienta G, Pascual J. Canonical and alternative MAPK signaling. Cell Cycle. 2007; 6(21):2628–2632. PMID: 17957138.

53. Praeger B. In-vitro studies of aging. Dermatol Clin. 1986; 4(3):359–369. PMID: 2424654.

54. 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(3):741–751. PMID: 15331399.

55. Quan T, He T, Shao Y, Lin L, Kang S, Voorhees JJ, Fisher GJ. Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin. Am J Pathol. 2006; 169(2):482–490. PMID: 16877350.

56. Quan T, He T, Voorhees JJ, Fisher GJ. Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its type-II receptor and inducing Smad7. J Biol Chem. 2001; 276(28):26349–26356. PMID: 11320083.

57. 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):415–424. PMID: 19641518.

58. Raghow R, Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest. 1987; 79(4):1285–1288. PMID: 3470308.

59. Rattner JB, Rao A, Fritzler MJ, Valencia DW, Yen TJ. CENP-F is a .ca 400 kDa kinetochore protein that exhibits a cell-cycle dependent localization. Cell Motil Cytoskeleton. 1993; 26(3):214–226. PMID: 7904902.

60. Robert L, Labat-Robert J, Robert AM. Physiology of skin aging. Pathol Biol (Paris). 2009; 57(4):336–341. PMID: 19046830.

61. Sardy M. Role of matrix metalloproteinases in skin ageing. Connect Tissue Res. 2009; 50(2):132–138. PMID: 19296304.

62. Seshadri T, Campisi J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science. 1990; 247(4939):205–209. PMID: 2104680.

63. Sheerin A, Thompson KS, Goyns MH. Altered composition and DNA binding activity of the AP-1 transcription factor during the ageing of human fibroblasts. Mech Ageing Dev. 2001; 122(15):1813–1824. PMID: 11557282.

64. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996; 273(5271):59–63. PMID: 8658196.

65. Sudel KM, Venzke K, Mielke H, Breitenbach U, Mundt C, Jaspers S, Koop U, Sauermann K, Knussman-Hartig E, Moll I, Gercken G, Young AR, Stab F, Wenck H, Gallinat S. Novel aspects of intrinsic and extrinsic aging of human skin: beneficial effects of soy extract. Photochem Photobiol. 2005; 81(3):581–587. PMID: 15623355.

66. Sundberg JP, King LE Jr. Morphology of hair in normal and mutant laboratory mice. Eur J Dermatol. 2001; 11(4):357–361. PMID: 11399545.

67. Svensson L, Aszodi A, Reinholt FP, Fassler R, Heinegard D, Oldberg A. Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. J Biol Chem. 1999; 274(14):9636–9647. PMID: 10092650.

68. Takeda U, Utani A, Wu J, Adachi E, Koseki H, Taniguchi M, Matsumoto T, Ohashi T, Sato M, Shinkai H. Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis. J Invest Dermatol. 2002; 119(3):678–683. PMID: 12230512.

69. Turchin I, Bernatsky S, Clarke AE, St-Pierre Y, Pineau CA. Cigarette smoking and cutaneous damage in systemic lupus erythematosus. J Rheumatol. 2009; 36(12):2691–2693. PMID: 19884279.

70. Uitto J. Connective tissue biochemistry of the aging dermis. Age-related alterations in collagen and elastin. Dermatol Clin. 1986; 4(3):433–446. PMID: 3521988.

71. Uitto J, Fazio MJ, Olsen DR. Molecular mechanisms of cutaneous aging. Age-associated connective tissue alterations in the dermis. J Am Acad Dermatol. 1989; 21(3 Pt 2):614–622. PMID: 2674224.

72. Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006; 168(6):1861–1868. PMID: 16723701.

73. Varani J, Schuger L, Dame MK, Leonard C, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ. Reduced fibroblast interaction with intact collagen as a mechanism for depressed collagen synthesis in photodamaged skin. J Invest Dermatol. 2004; 122(6):1471–1479. PMID: 15175039.

74. Warren R, Gartstein V, Kligman AM, Montagna W, Allendorf RA, Ridder GM. Age, sunlight, and facial skin: a histologic and quantitative study. J Am Acad Dermatol. 1991; 25(5 Pt 1):751–760. PMID: 1802896.

75. Wright WE, Shay JW. Telomere positional effects and the regulation of cellular senescence. Trends Genet. 1992; 8(6):193–197. PMID: 1496553.

76. Yaar M, Eller MS, Gilchrest BA. Fifty years of skin aging. J Investig Dermatol Symp Proc. 2002; 7(1):51–58.

77. Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and therapy. Br J Dermatol. 2007; 157(5):874–887. PMID: 17711532.

78. Yoon IK, Kim HK, Kim YK, Song IH, Kim W, Kim S, Baek SH, Kim JH, Kim JR. Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology. Exp Gerontol. 2004; 39(9):1369–1378. PMID: 15489060.