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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