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The Biology of Skin Ageing
dermal collagen. All of these changes parallel those seen in Figure 3: Ultraviolet Effects on Collagen Homeostasis
photoageing, but are generally less severe. The free radical theory of
ageing proposes that excesses of ROS, which result from aerobic
metabolism, accumulate over time, eventually leading to changes
associated with ageing.
30
In sun-protected skin, it is thought that ROS
ROS
generated with accumulation of time and other environmental stressors
(H
TβRII
2O2 OH)
may initiate molecular pathways very similar to those in sun-exposed
skin, with the ultimate result being loss and damage of collagen. EGF-R tyrosine phosphatase Smad2/Smad3- P
Effect of Sunscreens and Antioxidants in
Procollagen I
Photoageing and Intrinsic Ageing
EGF-R- P
EGF-R
(constitutively active)
(physiological)
The effects of various chemicals, antioxidants and drugs on these
pathways have been studied in order to better understand and study MAP kinase
the molecular pathways that underlie photoageing and intrinsic skin
(ERK, JNK, p38)
Smad7
ageing. Properly applied sunscreens that shield the skin from UVB and
AP-1
UVA rays can prevent UV-induced upregulation of MMPs and
subsequent collagen breakdown (unpublished data). Recognition of the MMPs
role that ROS play in photoageing and skin ageing has led to
considerable enthusiasm about the potential for antioxidant use in Collagen breakdown
prevention of these processes (see Figure 4). A few of the compounds
Ultraviolet (UV) irradiation induces expression of Smad7, which acts as a negative regulator
that have drawn more attention include N-acetylcysteine (NAC),
of Smad 2 and 3. This expression is mediated by activator protein 1 (AP-1), which has the
genistein, green tea, pomegranate and resveratrol.
10,31
NAC is a
direct effect of inducing matrix metalloproteinases (MMPs), which break down collagen, and
the indirect effect of downregulating collagen production through Smad7.
tripeptide that is eventually converted to glutathione, an endogenous
antioxidant. Topical application of 20% NAC to skin resulted in locally
Figure 4: Interventions that Can Affect
increased levels of reduced glutathione and elimination of oxidised
Collagen Pathways
glutathione. In addition, pre-treatment with NAC prevented UV-induced
extracellular signal-regulated protein kinase (ERK) activation and
subsequent upregulation of AP-1 and MMPs; therefore, NAC pre-
treatment was able to prevent UV-induced collagen breakdown.
10
The
effect of other antioxidants in preventing UV-induced induction of ROS Antioxidants
and subsequent collagen breakdown in human skin needs to be tested
Sunscreens
Sunscreens
individually. Topical pre-treatment with 5% genistein prevents UV-
induced activation of the EGF receptor in human skin, also preventing ROS
upregulation of AP-1 and MMPs, and subsequent collagen breakdown.
10
(H2O2 OH)
TβRII
EG
F
-R
Genistein inhibitors
Useful Interventions in Photoageing and
EGF-R tyrosine phosphatase Smad2/Smad3- P
Intrinsic Skin Ageing
While many cosmetics and cosmeceutical products purported to have
Procollagen I
medicinal or drug-like benefits claim to mitigate the clinical changes to EGF-R- P EGF-R
photoageing and ageing skin, only topical retinoids have objective
(constitutively active)
(physiological)
evidence supporting their use. Available topical retinoids include
MAP kinase
prescription tretinoin, adapalene and tazarotene, as well as over-the
(ERK, JNK, p38)
Smad7
counter retinol and retinal. These drugs are all vitamin A derivatives. The
Retinoids
first double-blind, randomised, vehicle-controlled trials investigating
tretinoin (all-transretinoic acid [tRA]) in photoaged skin were performed
AP-1
in the 1980s. These studies demonstrated improvements in surface
roughness, dyspigmentation and fine wrinkles.
32
Tretinoin has been
MMPs
shown to induce expression of type I and type III procollagen genes in
photodamaged human skin.
29
Increased procollagen production is Collagen breakdown
thought to result in increased deposition of new collagen in the dermis;
Certain interventions can interfere with the effects of ultraviolet (UV) irradiation on collagen.
after treatment with tretinoin for a mean of 2.3 years, the thickness of
Sunscreens prevent UV-induced collagen breakdown and downregulation of collagen
papillary dermal collagen almost doubles.
33
This layer of new dermal
production. Some antioxidants can ameliorate the effects of ROS on these pathways.
Genistein has been shown to prevent UV-induced activation of the epidermal growth factor
collagen is thought to be responsible for the clinical improvement
receptor (EGFR) in human skin. Topical retinoids result in increased procollagen formation
associated with use of tretinoin. While fewer investigations into the use
and reduced collagen breakdown.
of topical retinoids in intrinsic skin ageing have been performed, they
seem to have similar clinical and molecular effects.
5,34
an upregulation of MMPs, which degrade the fragmented collagen
matrix; subsequently, new and undamaged collagen is produced in the
Another treatment for improving the appearance of photoaged and dermis. Ultimately, CO
2
laser ablation has the effect of remodelling the
aged skin is carbon dioxide (CO
2
) laser ablation, which ablates the epidermis and dermis, resulting in a younger and tighter appearance
epidermis and stimulates a wound-healing response. Initially, there is of the skin.
35
While less invasive laser procedures are purported to
EUROPEAN DERMATOLOGY 41
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