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This lecture is exclusive for my web site. TREATMENT OF AGING SKIN: MOLECULAR CONSIDERATIONS AND HOW THEY INFLUENCE CLINICAL PRACTICE Erin Boh M.D.Ph.D.

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Presentation on theme: "This lecture is exclusive for my web site. TREATMENT OF AGING SKIN: MOLECULAR CONSIDERATIONS AND HOW THEY INFLUENCE CLINICAL PRACTICE Erin Boh M.D.Ph.D."— Presentation transcript:

1 This lecture is exclusive for my web site

2 TREATMENT OF AGING SKIN: MOLECULAR CONSIDERATIONS AND HOW THEY INFLUENCE CLINICAL PRACTICE Erin Boh M.D.Ph.D. Professor & Chairman Dept of Dermatology Tulane University Health Sciences Center New Orleans, LA, USA IACD; Lisbon,Portugal 2008

3 Cutaneous Aging Chronologic Aging Genetics Metabolic processes Oxidation Reduction Glycosylation Extrinsic Aging Environmental exposures UV irradiation Toxins Xenobiotics Mechanical stressors Intrinsic Aging Hormonal changes

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5 Dermal Matrix Homeostasis Synthesis TGF  /TGFR Fibroblast Collagen, elastin, proteoglycans, glycosaminoglycans Degradation Amiphregulin, betacellulin, epiregulin, TGFα EGFR AP-1 MMPs sequestration/degradation EGF R TGF

6 TGF-  History 1980’s: Murine studies with subcutaneous injection of TGF-  dose and time dependent increase in fibroblast proliferation increase in collagen synthesis increase in vasculogenesis Administration of antibodies to TGF-  markedly reduced collagen synthesis

7 SMAD-P Elastin Collagen GAGs TGFR TGF-  Signaling

8 Epidermal growth factor receptorAP-1 ↓ TGF ↑ MMPs

9 Cutaneous Aging Chronologic Aging Genetics Metabolic processes Oxidation Reduction Glycosylation Extrinsic Aging Environmental exposures Toxins Xenobiotics Mechanical stressors UV irradiation Intrinsic Aging Hormonal changes

10 Aging Process Intrinsic aging: dryness, laxity, fine wrinkles, atrophy

11 Aging Effects Extrinsic aging: fine/coarse wrinkling.pigmen- tary changes UVR Smoking Chemicals

12 Histologic changes of intrinsic aging  Changes in epidermal and dermal cellularity  Thinning of rete ridges  Degeneration of dermal matrix/decreased elasticity  Loss of glycoaminoglycans  Disorganization of microvasculare

13 Histologic changes of extrinsic Aging Clinical features of photoaged skin Wrinkles Furrows Dryness Loss of elasticity Dyspigmentation Histologic features of aged skin Reduced numbers of fibroblasts Reduced amount of extracellular matrix (ECM) Abnormal organization of ECM Atrophy of subcutis

14 Dermal Matrix Homeostasis Synthesis TGFß/TGFR Fibroblast Collagen, elastin, proteoglycans, glycosaminoglycans Degradation Amiphregulin, betacellulin, epiregulin, TGFα EGFR AP-1 MMPs sequestration/degradation EGF R TGF

15 Extrinsic Aging Ultraviolet Radiation UV irradiation disrupts the collagen matrix by two independent pathways Anabolic pathway Reduces procollagen synthesis Increase in non-functional latent TGFß protein Downregulate expression of TGFR Catabolic pathway Increases matrix metalloproteinases Auto-dimerization (activation) of EGFR Increase in AP-1 Inhibitors of TGFß Quan T, et al. American Journal of Pathology, vol 165, 9/2004 Xu Y, et al. Journal of Biological Chemistry, Vol 281, 9/2006 Wan Y, et al. Cellular Signalling, Vol 13, 2/2001

16 SMAD inhibition TGF inhibition

17 Epidermal growth factor receptorAP-1 ↓ TGF ↑ MMPs

18 SMAD inhibition

19 Molecular Consequences of Photoaging UVR ROS   TbRII receptor mRNA   TGF ß ROS   SMAD 7 mRNA SMAD 7   TGF  ROS   AP-1(via c-Jun) ROS   EGFR Decreased collagen, elastin, proteoglycan synthesis Increased matrix metalloproteinase synthesis Upregulate MMPs Downregulate TGF 

20 Molecular Consequences of Photoaging UVR  ROS  ↑c-Jun ↑Activator protein 1 (AP-1) & NF-κB  ↑ MMP ( AP-1 (c-Fos & c-Jun) MMPs ( collagenase, gelatinase, Stromelysin-1) Induces TIMP Increases elastin Increases polar gag Decreased collagen, elastin, proteoglycan synthesis

21 Photoaging Free radical theory of aging & photoaging UVR  ROS  cellular damage Repair mechanisms: Redox enzymes Antioxidants

22 External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1 O 2 or O 2 — NADH - /NADPH Tryptophan Riboflavin Trans-urocanic acid 2 O 2 -- + 2H + → H 2 O 2 + O 2 H 2 O 2 + Fe ++ → OH + OH -- + Fe +++

23 External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1 O 2 or O 2 — NADH - /NADPH Tryptophan Riboflavin Trans-urocanic acid 2 O 2 -- + 2H + → H 2 O 2 + O 2 H 2 O 2 + Fe ++ → OH + OH -- + Fe +++

24 External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1 O 2 or O 2 — NADH - /NADPH Tryptophan Riboflavin Trans-urocanic acid 2 O 2 -- + 2H + → H 2 O 2 + O 2 H 2 O 2 + Fe ++ → OH + OH -- + Fe +++

25 External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1 O 2 or O 2 — NADH - /NADPH Tryptophan Riboflavin Trans-urocanic acid 2 O 2 -- + 2H + → H 2 O 2 + O 2 H 2 O 2 + Fe ++ → OH + OH -- + Fe +++

26 External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1 O 2 or O 2 — NADH - /NADPH Tryptophan Riboflavin Trans-urocanic acid 2 O 2 -- + 2H + → H 2 O 2 + O 2 H 2 O 2 + Fe ++ → OH + OH -- + Fe +++ Lipid peroxidation DNA damage

27 External Environmental Aging Ultraviolet Radiation UVR  ROS directly interact with the phosphorylation status of growth factor signal transduction cascades Specific growth factor functions altered ↓ cellular antioxidants Induces apoptosis Alters cross linking of collagen ↑ collagen degradation ↑ DNA damage

28 Repair mechanisms: Redox enzymes -Superoxide dismutase -Catalase -Glutathione reductase -GSH peroxidase Endogenous antioxidants

29 ANTIOXIDANTS Endogenous Glutathione Vitamins C,E,A Ubiquinol Oxidative enzymes: catalase,superoxide dismutase,GSH peroxidases Exogenous Vitamin A derivatives Vitamin C,B,E Co-enzyme Q AHA Alpha lipoic acid Peptides: Cu; NH 2

30 Treatment of Photoaged Skin Reversal of photodamage -Replacement of antioxidants -Absorption of UVR by chromophores - Replacement of growth factors -Stimulation of new dermal matrix Upregulation of new collagen synthesis Inhibition of collagen breakdown

31 Treatment of Photoaged Skin Endogenous Glutathione Vitamins C,E,A Ubiquinol Oxidative enzymes: catalase,superoxide dismutase,GSH peroxidases Topical formulations Vitamin A derivatives Vitamin C,B,E Co-enzyme Q AHA Alpha lipoic acid Peptides: Cu; NH 2 Replacement of antioxidants

32 Treatment of Photoaged Skin  Agent must be in stable formulation  Must penetrate/be absorbed in sufficient concentrations  Must release reducing equivalents Effective Topical Antioxidants

33 VITAMIN A DERIVATIVES Vitamin A ( retinoic acid; retinol; retinaldehyde) Tretinoin Adapalene Tazarotene Treatment of Photoaged Skin: Replacement of antioxidants

34 VITAMIN A DERIVATIVES Antioxidant Antiinflammatory Upregulation of new collagen: Histologic restoration of photodamaged skin Normalization of cellular atypia Normalization of cellular architecture Stimulates new collagen/elastin Stimulates angiogenesis Normalizes gag synthesis Treatment of Photoaged Skin Br J Dermatol 2007 Br J Dermatol 2007;157: 874-887

35 MOLECULAR MECHANISMS OF PHOTOAGING UVR changes Induces c-Jun ÞMMP Induces TIMP Induces elastin mRNA Increases gag ( -SO4) Tretinoin effects Inhibits c-Jun induction: no ↑ MMP No effect on TIMP Inhibits elastin mRNA Normalizes gag

36 TRETINOIN: Net Effects Thin atrophic epidermis with atypical architecture & cellularity Altered dermis Net Effects: Molecular Inhibition of collagen breakdown New collagen synthesis Increased dermal ECM

37 TRETINOIN: Net effects Net Effects: Clinical Smooth skin Less pigmentary alterations Less wrinkling/laxity of skin

38 ANTIOXIDANTS Vitamin C Vitamin E CoQ-10 Alpha lipoic acid Botanicals: Soy isoflavones Pycnogenol Green tea extracts TREATMENT OF PHOTOAGED SKIN: Replacement of antioxidants

39 Antioxidants VITAMIN C Cofactor for collagen synthesis Reduces UVR induced changes Photoprotection Some formulations unstable VITAMIN E Naturally occurring Inhibits UVR induced lipid peroxidation Replenishes Vitamin C, GSH Dermatologic Therapy 2007;20:314-321

40 Antioxidants Alpha Lipoic Acid Involved in oxidative metabolism ROS scavenger ( inhibits lipid peroxidation) ß NF-  B Chelates metals Regenerates vitamins E & C Treatment of Photoaged skin Br J Dermatol 2003;149: 841-9

41 BOTANICALS Isoflavones: Antioxidant Increases skin thickness May inhibit melanosome phago- cytosis Pycnogenol: Reduces Vit. C Green tea extracts: (polyphenols) Anti-inflammatory; inhibits UVR damage Allantoin: Antiinflammatory promotes repair Dermatologic Therapy 2007;20:322-329 Dermatplogic Therapy 2007;20:343-349 PhotodermatolPhotoimmunol Photomed 2007;23:155-162

42 Replacement of Growth Factors/Stimulate cytokines Transforming growth factor  Epidermal growth factor (receptor) Keratinocyte growth factor Fibroblast growth factor Platelet-derived growth factor Vascular endothelial growth factor Dermatologic Therapy 2007;20:350-359 Dermatologic Surgery 2006;32:618-625 Treatment of Photoaged skin

43 Topical TGF-  Products Well tolerated Minimizes appearance of rhytides when compared to Vitamin C Few studies at molecular level of reversal of photodamage Dermatolog Surg 2006;32:618-625 Dermotologic Therapy 2007;20: 350-359 TNS Recovery Complex Bio-restoratiive Skin Cream Cell rejuvenation serum ( CRS)

44 CLINICAL STUDIES WITHMULTIPLE GROWTH FACTOR COSMECEUTICALS TNS RECOVERY COMPLEX ® (SkinMedica) Study Design: 14 Female subjects 2 Months twice daily Facial wrinkle scoring (9-point score) Silicon replica Histology J Cosmetic & Laser Ther 2003, 5: 25-34

45 CLINICAL STUDIES WITH MULTIPLE GROWTH FACTOR COSMECEUTICALS BIO-RESTORATIVE SKIN CREAM WITH PSP ® (NEOCUTIS) Study Design: 18 Female subjects 2 Months twice daily, followed by 2 week wash-out Facial wrinkle scoring (5-point score) J Drugs Dermatol 2007, 6:197-201

46 Proposed Mechanism of Action of Growth Factor Cosmeceuticals Large hydrophilic molecules unlikely to penetrate skin barrier but may penetrate through follicles, sweat glands and damaged skin Produce epidermal signaling cytokines which affect dermal fibroblasts Mechanism is not elucidated

47 CONCLUSIONS Human growth factor cosmeceuticals are effective for skin rejuvenation Multiple growth factor cosmeceuticals are particularly beneficial as demonstrated in several clinical studies Growth factor cosmeceuticals may be also helpful to improve outcome after cosmetic and dermatologic procedures Additional studies warranted to further elucidate promising technology: double blinded placebo controlled studies -both clinical and at molecular level

48 Topical treatment of Photoaged Skin Sunscreens as protection against ongoing damage and combination of Tretinoin Alpha hydroxy acids Vitamin C Vitamin E Botanical antioxidants Growth factor cosmeceuticals

49 QUESTIONS TO BE ASKED OF COSMECEUTICALS Can agent penetrate? Does agent have MOA in target tissue? Is there peer-reviewed data to support claim?

50 PERSPECTIVES FOR PHOTOAGING Provide patient with sound reasonable advise about cosmeceuticals Prospective objective studies are needed

51 CONCLUSIONS Popularity of noninvasive treatments of photoaging ( cosmeceuticals) useful when care is taken to construct a treatment regimen based on understanding of the molecular mechanisms in place Patient needs to have realistic expectations and know limitations of products

52 CONCLUSIONS Assess the patient relative to what bothers patient Recognize that each of these therapies offers mild to modest effects but may prove more efficacious when used in combination

53 Pentapeptide( KTTKS) Lys-Thr-Thr- Lys-Ser ↑collagen synthesis Copper Peptides Wound healing ↑collagen synthesis

54 Environemental Affects Upon Cutaneous Aging External Environmental Factors UVRUVR TobaccoTobacco Internal Environmental Factor Estrogen statusEstrogen status Chronologic Aging Oxidative metabolism


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