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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. Professor & Chairman Dept of Dermatology Tulane University Health Sciences Center New Orleans, LA, USA IACD; Lisbon,Portugal 2008 Cutaneous Aging Chronologic Aging Genetics Metabolic processes • Oxidation • Reduction • Glycosylation Extrinsic Aging Environmental exposures • • • • UV irradiation Toxins Xenobiotics Mechanical stressors Intrinsic Aging Hormonal changes Dermal Matrix Homeostasis Synthesis TGF/TGFR Fibroblast Collagen, elastin, proteoglycans, glycosaminoglycans Degradation Amiphregulin, betacellulin, epiregulin, TGFα EGFR AP-1 MMPs sequestration/degradation 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 TGF- Signaling SMAD-P Elastin Collagen GAGs TGFR Epidermal growth factor receptor AP-1 ↓TGF ↑MMPs Cutaneous Aging Chronologic Aging Genetics Metabolic processes • Oxidation • Reduction • Glycosylation Extrinsic Aging Environmental exposures • • • • Toxins Xenobiotics Mechanical stressors UV irradiation Intrinsic Aging Hormonal changes Aging Process Intrinsic aging: dryness, laxity, fine wrinkles, atrophy Aging Effects Extrinsic aging: fine/coarse wrinkling.pigmentary changes UVR Smoking Chemicals 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 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 Dermal Matrix Homeostasis Synthesis TGFß/TGFR Fibroblast Collagen, elastin, proteoglycans, glycosaminoglycans Degradation Amiphregulin, betacellulin, epiregulin, TGFα EGFR AP-1 MMPs sequestration/degradation 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 SMAD inhibition TGF inhibition Epidermal growth factor receptor AP-1 ↓TGF ↑MMPs SMAD inhibition Molecular Consequences of Photoaging UVR Downregulate TGF Upregulate MMPs 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 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) Decreased collagen, Induces TIMP elastin, proteoglycan Increases elastin synthesis Increases polar gag Photoaging Free radical theory of aging & photoaging UVR ROS cellular damage Repair mechanisms: Redox enzymes Antioxidants External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1O2 or •O2— • NADH-/NADPH • Tryptophan • Riboflavin • Trans-urocanic acid 2 •O2-- + 2H+ → H2O2 + O2 H2O2 + Fe++ → OH• + OH-- + Fe+++ External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1O2 or •O2— • NADH-/NADPH • Tryptophan • Riboflavin • Trans-urocanic acid 2 •O2-- + 2H+ → H2O2 + O2 H2O2 + Fe++ → OH• + OH-- + Fe+++ External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1O2 or •O2— • NADH-/NADPH • Tryptophan • Riboflavin • Trans-urocanic acid 2 •O2-- + 2H+ → H2O2 + O2 H2O2 + Fe++ → OH• + OH-- + Fe+++ External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1O2 or •O2— • NADH-/NADPH • Tryptophan • Riboflavin • Trans-urocanic acid 2 •O2-- + 2H+ → H2O2 + O2 H2O2 + Fe++ → OH• + OH-- + Fe+++ External Environmental Aging Ultraviolet Radiation Photo-Redox Reactions UV chromophore → 1O2 or •O2— • NADH-/NADPH • Tryptophan • Riboflavin • Trans-urocanic acid 2 •O2-- + 2H+ → H2O2 + O2 H2O2 + Fe++ → OH• + OH-- + Fe+++ Lipid peroxidation DNA damage 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 Repair mechanisms: Redox enzymes -Superoxide dismutase -Catalase -Glutathione reductase -GSH peroxidase Endogenous antioxidants 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; NH2 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 Treatment of Photoaged Skin Replacement of antioxidants 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; NH2 Treatment of Photoaged Skin Effective Topical Antioxidants Agent must be in stable formulation Must penetrate/be absorbed in sufficient concentrations Must release reducing equivalents Treatment of Photoaged Skin: Replacement of antioxidants VITAMIN A DERIVATIVES Vitamin A ( retinoic acid; retinol; retinaldehyde) Tretinoin Adapalene Tazarotene Treatment of Photoaged Skin VITAMIN A DERIVATIVES Antioxidant Antiinflammatory Upregulation of new collagen: Histologic restoration of photodamaged skin Br J Dermatol 2007 Br J Dermatol 2007;157: 874-887 Normalization of cellular atypia Normalization of cellular architecture Stimulates new collagen/elastin Stimulates angiogenesis Normalizes gag synthesis 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 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 TRETINOIN: Net effects Net Effects: Clinical Smooth skin Less pigmentary alterations Less wrinkling/laxity of skin TREATMENT OF PHOTOAGED SKIN: Replacement of antioxidants ANTIOXIDANTS Vitamin C Vitamin E CoQ-10 Alpha lipoic acid Botanicals: Soy isoflavones Pycnogenol Green tea extracts 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 Treatment of Photoaged skin Antioxidants Alpha Lipoic Acid Involved in oxidative metabolism ROS scavenger ( inhibits lipid peroxidation) ß NF-B Chelates metals Regenerates vitamins E & C Br J Dermatol 2003;149: 841-9 BOTANICALS Isoflavones: Antioxidant Increases skin thickness May inhibit melanosome phagocytosis 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 Treatment of Photoaged skin 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 Topical TGF- Products • • • Well tolerated Minimizes appearance of rhytides when compared to Vitamin C Few studies at molecular level of reversal of photodamage TNS Recovery Complex Dermatolog Surg 2006;32:618-625 Dermotologic Therapy 2007;20: 350-359 Bio-restoratiive Skin Cream Cell rejuvenation serum ( CRS) Averaged Improvement (%) CLINICAL STUDIES WITHMULTIPLE GROWTH FACTOR COSMECEUTICALS 15 Peri-orbital Peri-oral 10 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 5 0 After 2 months twice daily TNS RECOVERY COMPLEX® (SkinMedica) CLINICAL STUDIES WITH MULTIPLE GROWTH FACTOR Averaged Improvement (%) COSMECEUTICALS 20 Peri-orbital 15 Study Design: 18 Female subjects Peri-oral 2 Months twice daily, followed by 2 week wash-out 10 Facial wrinkle scoring (5-point score) 5 J Drugs Dermatol 2007, 6:197-201 0 30 60 74 Time (days) BIO-RESTORATIVE SKIN CREAM WITH PSP® (NEOCUTIS) 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 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 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 QUESTIONS TO BE ASKED OF COSMECEUTICALS Can agent penetrate? Does agent have MOA in target tissue? Is there peer-reviewed data to support claim? PERSPECTIVES FOR PHOTOAGING Provide patient with sound reasonable advise about cosmeceuticals Prospective objective studies are needed 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 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 Pentapeptide( KTTKS) Lys-Thr-ThrLys-Ser ↑collagen synthesis Copper Peptides Wound healing ↑collagen synthesis Environemental Affects Upon Cutaneous Aging Internal Environmental Factor •Estrogen status Chronologic Aging Oxidative metabolism External Environmental Factors •UVR •Tobacco