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DOI: 10.1111/j.1468-3083.2010.03963.x
REVIEW ARTICLE
Skin ageing
E. Kohl,†,* J. Steinbauer,† M. Landthaler,† R.-M. Szeimies‡
†
Department of Dermatology, Regensburg University Hospital, Regensburg, and ‡Department of Dermatology and Allergology,
Hospital Vest, Recklinghausen, Germany
*Correspondence: E. Kohl. E-mail: elisabeth.kohl@klinik.uni-regensburg.de
Abstract
Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing
is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also
referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the
ageing process in sun-exposed areas. Despite their morphological and pathophysiological differences, intrinsic and
extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of
matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils
prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive
feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have
furthered the development of various therapeutic and preventive strategies.
Received: 13 May 2010; Accepted: 14 December 2010
Keywords
extrinsic skin ageing, intrinsic skin ageing, matrix metalloproteinases, photoageing, retinoids, UV radiation
Conflict of interest
None declared.
Introduction
Skin ageing, a highly complex but not yet fully understood process, is particularly interesting because of the continuously increasing life expectancy in many countries. Several theories have been
developed to comprehend this progressive process. Ageing may be
considered as the accumulation of different deleterious changes in
cells and tissues. These changes may progressively impair biological functions, increase the risk of developing diseases and ultimately lead to death.1 Up to now, no integrative concept exists
connecting the ageing models evolved so far.
Intrinsic and extrinsic skin ageing
Pathomechanisms of intrinsic skin ageing
Intrinsically aged skin is usually found in sun-protected areas.
Photoageing may be considered a superposition of chronological
skin ageing by UV-radiation. Skin may serve as a model organ for
investigating both endogenous and exogenous ageing models.
Extrinsic and intrinsic skin ageing show similarities in molecular
mechanisms.
The following aspects are discussed in several theories on intrinsic skin ageing: Cellular ageing (Hayflick-Limit) and shortening of
telomeres, mutations of mitochondrial DNA, oxidative stress,
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genetic mutations and decrease of several hormone levels.2
According to the free radical theory of ageing, reactive oxygen species (ROS), primarily arising from oxidative cell metabolism, play
a major role in both chronological ageing and photoageing.3
Despite several antioxidative mechanisms, which deteriorate with
increasing age, abound ROS damage cellular components. This
damage leads to increasing ROS and decreasing antioxidative
capacities and finally to cellular ageing.2,4 ROS in extrinsic and
intrinsic skin ageing may be assumed to induce the transcription
factor c-Jun via MAPK (mitogen-activated protein kinases). This
induction activates the decisive transcription factor AP-1 (activator protein 1), leads to the expression of matrix metalloproteinases
MMP-1 (interstitial collagenase), MMP-3 (stromelysin 1), and
MMP-9 (gelatinase b) and prevents the expression of procollagen1.5 In accordance with these results, elevated levels of partially
degraded collagen are present in intrinsically aged skin similar to
photoaged skin. Recently, an in vivo study has indicated that
reduced expression of the connective tissue growth factor (CTGF)
and reduced transforming growth factor (TGF)-b ⁄ Smad signalling
are probably responsible for the loss of type I procollagen expression in intrinsically aged skin.6
Intrinsic skin ageing is strongly influenced by hormonal
changes.7 Production of sex hormones in the gonads, the pituitary,
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Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
Kohl et al.
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and adrenal glands already gradually declines in the mid-twenties.
Oestrogens and progesterone decay in line with the menopause. In
particular, the deficiency in oestrogens and androgens cause dryness, wrinkling, epidermal atrophy, collagen breakdown and loss
of elasticity.8,9
mutations of mitochondrial DNA lead to dysfunctional oxidative
phosphorylation. Thus, more ROS are generated, causing even
more mutations.15 A causative relationship must be assumed for
the depletion of mitochondrial DNA, resulting in oxidative stress
and increased expression of MMP-1.16
Pathomechanisms of photoageing
Role of telomeres Telomeres consisting of 1000-fold tandem
repeats of TTAGGG in humans form the chromosome ends. Telomeres do not encode any gene products and constitute the last
7000–12 000 base pairs. Telomere length varies with species and
decreases with increasing age.17
Telomeres consist of a double-strand region composed of
TTAGGG repeats and a much shorter single-strand 3¢ overhang at
the distal end. Telomeres form a 3-dimensional structure (t-loop)
that is required for telomere capping. The t-loop is secured by
insertion of the 3¢ overhang into the proximal double-stranded
DNA. T-loops prevent the chromosome ends to be recognized as
double-strand breaks, defending them from instability as a fusion
of chromosomes. A complete replication of the final bases by
DNA-polymerase is not possible. For this reason, telomeres
shorten with each cell division by approximately 100 base pairs.18
Therefore, the number of cell divisions is confined to 50–70
because of critical telomere shortening.19
Critical shortening of telomeres induces disruption of the t-loop
configuration, exposing the 3¢ overhang. This process initiates
DNA-damage response, entailing to apoptosis, senescence or cell
cycle arrest.20
Besides shortening telomeres with each round of cell division,
UV-radiation or other DNA-damage may lead to loop disruption,
exposing the TTAGGG tandem repeat sequence. This process elicits the above-mentioned DNA-damage response, indicating the
possible existence of a common mechanism for intrinsic ageing
and photoageing.21
UV-exposure particularly damages telomeres because of their
higher number of TT- and G-bases compared with the other part
of the chromosome. UV-radiation particularly targets TT- and
G-bases, possibly destabilizing the t-loop configuration and activating the common signalling pathway.22
The impact of telomeres on the aetiopathology of photoageing
was also put into question.23 Telomere lengths in photoaged and
photoprotected skin did not differ; altogether, telomere length was
shorter in the epidermis than in the dermis.24 Expression of telomerase is maintained in early embryonic, malignant and germ
cells. Telomerase acts as a maintenance mechanism of telomere
length, synthesizing TTAGGG sequences.23 Contrary to most
somatic cells, expression of telomerase is maintained in the hematopoietic system and in the gastrointestinal tract. Evidence suggests
expression of telomerase in the keratinocytes of rapidly regenerating epidermis.25 The epidermis in situ showed a mean telomere
loss of 25 bp per year. A telomerase-based mechanism to maintain
telomere length in keratinocytes must be assumed because of
the high proliferation rate of keratinocytes in contrast to slowly
Extrinsic skin ageing primarily arises from UV-light exposure.
Approximately 80% of facial skin ageing is attributed to UV-exposure.10 Further relevant exogenous factors are exposure to tobacco
smoke, airborne particulate matter, infrared radiation, ozone and
malnutrition. Premature skin ageing or photoageing are synonyms
for extrinsic skin ageing.
The biological effects of UV-radiation are based on light absorption in chromophores and the subsequent conversion of energy in
chemical reactions. UVA ⁄ UVB-radiation contribute to biological
effects, resulting in skin ageing and photocarcinogenesis. The exact
action spectrum, i.e., the biological effects depending on wavelengths, remains unclear. Short wave UVB is mainly absorbed in
the epidermis, generating DNA-damage by forming photocarcinogenic cyclobutane pyrimidine dimers (CPDs) and 6,4-photoproducts. UVA-light is absorbed by cellular chromophores, such as
urocanic acid, melanin precursors and riboflavin. These lightexposed chromophores generate ROS, which damage lipids, proteins and DNA. UVA-light is exceptionally relevant in photoageing
because of its high penetration depth.11
Mutations of mitochondrial DNA The main endogenous source
of ROS is mitochondria, and ROS are built from approximately
1% of the oxygen consumed in the mitochondria. ROS, in addition to their physiological role as signalling molecules, lead to oxidative stress after exhaustion of cellular defence mechanisms.
Because of their proximity, ROS generated in the respiratory chain
are particularly important for mitochondrial (mt) DNA. The
human mtDNA consists of up to 10 copies of a double-stranded
circular DNA-molecule comprising 16 559 base pairs, which
encodes proteins of the respiratory chain. mtDNA shows considerably higher mutation rates than nuclear DNA because of its inefficient recognition and repair mechanisms.12
Mutations of mitochondrial DNA are important for ageing
processes, photoageing and various neurological diseases. Photoaged skin shows more mutations in mtDNA than sun-protected
skin.13 The most frequent mitochondrial mutation is a large-scale
4977 base-pair deletion termed ‘common deletion’, whose induction is directly related to chronic UVA-exposure. In vivo repetitive
exposure of previously unirradiated skin to physiological doses of
UVA-light increased the level of common deletion in human skin
by 40%. The 4977 bp-deletions persisted and were detectable even
months after cessation of irradiation. The levels of common deletion continued to increase and partly showed an up to 32-fold
accumulation 16 months after irradiation.14 These observations
are in accordance with the theory proposing that ROS-induced
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Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
Skin ageing
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proliferating fibroblasts with a reported telomere loss of 25 bp per
year. The evidence for functionally active telomerase in human
epidermis and the lack of considerable telomere loss of keratinocytes and fibroblasts suggest that telomere loss does not play a key
role in intrinsic skin ageing.23
Matrix metalloproteinases and signal transduction pathways As
a major structural protein of the extracellular matrix (ECM), type
I collagen is secreted by fibroblasts, forming more than 90% of the
dry weight of the dermis. Besides, MMPs are secreted, hydrolyzing
ECM proteins, such as collagen fibres. After exposure to suberythematous UVB-doses, sustained elevations of MMPs were
assessed.26 MMP-1 initiates cleavage of type I collagen and is thus
particularly important for degrading the ECM.
Additionally, UV-exposure involves considerably decreased collagen production. Photoaged skin is designated with a collagenous
matrix fragmented by MMPs. UV-induced oxidative stress initiates signalling cascades via the activation of several cell surface
receptors. This activation results in the degradation of the ECM
and in the down-regulation of neocollagenesis. Receptor activation
effects stimulation of MAP-kinases p38, JNK (c-Jun amino-terminal kinase), and ERK (extracellular signal-regulated kinases), consequently inducing the transcription factor AP-1. AP-1 induces
collagen degradation by up-regulation of MMP-1, MMP-3 and
MMP-9.26 In addition, procollagen synthesis is inhibited by the
UV-induced transcription factor AP-1. Increased transcription of
AP-1 inhibits the effects of TGF-b (transforming growth factor b),
a cytokine promoting collagen production.27 Extracellular matrix
degradation is further enhanced by UV-induced activation of the
transcription factor NF-jB. This factor stimulates the expression
of MMPs and several cytokines and enforces UV-response by
activating respective cell surface receptors.
UV-induced elevated levels of MMPs are not accompanied by
the compensatory augmented production of their physiological
inhibitors, the TIMPs (tissue inhibitor of matrix metalloproteinases). Induction of MMPs may be effected by UVA and UVB.28
Expression of MMP-1, MMP-3 and MMP-9 occurs in both keratinocytes and fibroblasts. In vivo studies have shown that MMPs in
UV-exposed skin (solar simulated UV irradiation) primarily derive
from epidermal keratinocytes and diffuse into the dermis; here,
they bind directly to ECM.29
Mechanical tension and ECM Loss of mechanical tension contributes to molecular changes detectable in aged skin. Beyond the
cellular ageing process of fibroblasts, reduced neocollagenesis may
be ascribed to the reduced mechanical stimulation of fibroblasts.
In aged skin, fibroblasts collapse because of the loss of mechanical
tension caused by the accumulation of fragmented collagen and
concomitant loss of binding sites between intact collagen and
fibroblasts. This process concurs with an increase in MMPs, the
intracellular oxidative level, protein oxidation, the transcription
factor AP-1 and with a reduction of collagen production, resulting
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in a self-perpetuating cycle (see Fig. 1).30 Degradation of elastic
fibres is also relevant in skin ageing processes and particularly in
wrinkle formation. The findings obtained in animal experiments
suggest repetitive UVB-exposure as a cause of wrinkle formation
through loss of skin elasticity. The expression of fibroblast elastase
is stimulated by UVB-induced cytokine secretion of keratinocytes.
Up-regulated activity of fibroblast elastase damages elastic fibres
facilitating wrinkle formation.31
Within the framework of UV-exposure (solar simulated UV
irradiation), infiltrating neutrophil granulocytes release MMP-1,
MMP-8 (neutrophil collagenase), MMP-9 and neutrophil elastase
and participate in the degradation of the ECM. Neutrophil granulocytes are assumed to play a critical role in the pathogenesis of
photoageing.32
Vascular alterations Skin ageing also involves alterations of
dermal vascularization. In the papillary dermis of photoaged skin,
both vessel size and density are significantly decreased. However,
intrinsically aged skin only shows a decrease in vessel size because
the density of dermal blood vessels is age-independent.33
Imbalance of the angiogenesis inhibitor thrombospondin-1
(TSP-1) and the vascular endothelial growth factor (VEGF) is
of particular importance in UV-induced vascular changes. Acute
Figure 1 This model schematically depicts factors of pathogenic
relevance for skin ageing. The induction of matrix metalloproteinases is of particular importance as they degrade collagen and
other components of the extracellular matrix (ECM). Mainly UVinduced reactive oxygen species (ROS) and DNA damage lead to
increased induction of matrix metalloproteinases in keratinocytes
and fibroblasts. Proteolytic enzymes such as elastase and matrix
metalloproteinases derived from neutrophil granulocytes contribute to the degradation of the ECM. Besides, UV-exposure
directly stimulates the production of elastase in fibroblasts. As a
result, partially degraded collagen and reduced mechanical tension of fibroblasts inhibit neocollagenesis. Reduced mechanical
tension leads to further production of ROS, which again results in
increased expression of matrix metalloproteinases.
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Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
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UVB-irradiation results in pronounced generation of immature
vessels, possibly arising from the down-regulation of TSP-1 and
the up-regulation of VEGF.34 UVB-irradiated transgenic mice with
overexpression of TSP-1 showed decreased skin vascularization as
well as reduced wrinkle formation compared with the control
group.35
The causes of the aforementioned reduction of dermal vessels in
photoaged skin in contrast to the proangiogenic effects of acute
UV-exposure require further investigations. Altered ECM in photoaged skin is assumed to allow the regression of dermal vessels.33
Protein oxidation Ageing cells show accession of oxidized proteins and consequently declining proteasome activities.36 Activity
of the proteasome, a multicatalytic protease that degrades oxidized proteins, declines with age.37 Protein oxidation results
from UV-induced depletion of antioxidant enzyme expression.
The epidermis of photodamaged skin shows significantly lower
levels of antioxidant enzymes than photoprotected skin. As the
levels of antioxidant enzymes in the dermis are considerably
lower than those in the epidermis, photoaged skin shows
accumulation of oxidized proteins in the upper dermis. In
combination with the lower proliferative activity of fibroblasts
compared with that of keratinocytes, the low enzyme levels may
explain the pattern of distribution of oxidized proteins.37 Accumulation of oxidized and cross-linked proteins results in the
aggregation of proteins and lipofuscin, progressively inhibiting
all proteasome activities. The quantity of dermal oxidized proteins correlates well with the severity of the clinical features of
photoageing.37
Figure 2 Deep furrows, solar elastosis, focal hypopigmentation
and solar lentigines in the face of a 66-year-old patient with
Fitzpatrick’s skin type II.
Clinical and histological changes in intrinsically and
extrinsically aged skin
Intrinsically aged skin is uniformly pigmented, showing loss of
elasticity, cigarette paper-like wrinkling, and rarefied hair follicles,
sweat glands and sebaceous glands.
The cumulative UV-dose and the Fitzpatrick skin type assign
the degree of sun-induced cutaneous changes. People with skin
types I and II show atrophic skin changes with focal depigmentation, epidermal atrophy, ephelides and pseudoscars and may
develop malignant or non-malignant skin cancer. By contrast,
people with skin types III and IV show diffuse irreversible hyperpigmentation, leathery appearance, deep wrinkles and lentigines
(Figs 2–4).
Because of the distinct extension of cell cycles, the epidermis is
renewed much slower in elderly people. The epidermal turnover
rate is up to 50% lower in the eighth decade of life. Moreover,
intrinsically aged skin shows epidermal atrophy, which particularly
affects the stratum spinosum, ranging from 10% to 50%.38
From the age of 30 onwards, the number of melanocytes abates
by 8% to 20% per decade.39 The notably fewer Langerhans cells
present show morphological alterations and are functionally
impaired. The dermis of photoprotected aged skin shows fewer
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Figure 3 Deep perioral wrinkles of the same patient with a
10-year history of smoking cigarettes.
mast cells and fibroblasts than photoprotected young skin, and
collagen fibres and elastic fibres are rarefied.40 Collagen synthesis
declines by 30% in the first 4 years of menopause, then by 2%
annually.41
The epidermis in sun-exposed areas is thicker than in intrinsically aged skin, whereas severe photodamage elicits epidermal
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Similar to UV-radiation, IRA is capable of inducing ECM degradation, thus accelerating the skin ageing process. Already in
1982 was exposure to IRA found to result in dermal damage,
resembling solar elastosis.47 IRA radiation causes ROS formation
in the mitochondria and increases expression of MMP-1 and
MMP-9. Antioxidants that specifically target the mitochondria
[MitoQ (mitoquinone)] block the IRA-induced expression of
MMP-1 in human fibroblasts, whereas the UVA ⁄ UVB-induced
increased expression of MMP-1 remains unaffected.48
Besides the increased expression of MMP-1, IRA-exposure
decreases the production of procollagen 1.49 Similar to UV-exposure, acute exposure to IRA elicits neoangiogenesis and accumulation of infiltrating inflammatory cells.50
Prevention and therapy
Figure 4 The back of the hands of a 23-year-old woman (top left
corner) without any signs of photoageing and of a 46-year-old
woman (top right corner) with lentigines and fine wrinkles. On the
bottom right, the back of the hand of a 61-year-old woman with
lentigines and wrinkles and, on the bottom left, the back of the
hand of an 83-year-old woman showing loss of subcutaneous
fat, lentigines, hypopigmented spots, deep wrinkles and atrophy.
Inorganic and organic sunscreens
atrophy.42 Sun-induced molecular effects are primarily located in
the dermis and the dermoepidermal junction. Histopathologically,
photoaged skin is distinguished by solar elastosis, i.e., the accumulation of degraded elastic tissue in the dermis. Elastotic material
consists of elastin, fibrillin, glycosaminoglycans, particularly hyaluronic acid, and versican, a large chondroitin sulphate proteoglycan. The pathogenesis of solar elastosis is not yet fully understood
but is assumed to derive from both degradation and de novo synthesis.43
Photoprotection is essential for preventing UV-induced premature
skin ageing. In vivo studies have indicated that the regular application of sunscreen may avoid or at least diminish UV-induced
epidermal and dermal changes.51 Topical sunscreens are divided
into inorganic (formerly referred to as physical) and organic sun
protection (formerly referred to as chemical).
Inorganic sunscreens as titanium dioxide and zinc oxide reflect,
scatter, or absorb UV-radiation depending on the particle size and
the wavelength of the light. Zinc oxide and titanium dioxide neither have any skin-irritating or skin-sensitizing properties nor penetrate into the layers below the stratum corneum. Modern
micronized forms show a decreased particle size of 10–50 nm,
offering more transparent and cosmetically appealing formulations. Organic sunscreens absorb UV-radiation, whereby the
agent’s electrons reach an excited state. For a more detailed
description of this topic, we refer to several excellent reviews.52,53
Skin ageing induced by other exogenous factors
Antioxidants
Tobacco smoking Besides UV-exposure, alcohol consumption,
skin type and gender, exposure to tobacco smoke is a major factor
contributing to premature skin ageing.44 Several studies have indicated that cigarette smoking furthers wrinkle formation. Analysis
of skin surface structure showed that people with a smoking history of at least 35 pack years showed significantly deeper wrinkles
than non-smokers, yet line density was decreased compared with
non-smokers.45 Similar to UV-exposure, nicotine abuse induces
expression of MMPs degrading ECM in human skin.46
Infrared radiation Infrared (IR) radiation (k = 760 nm to
1 mm) comprises 54.3% of total incident solar energy and may be
subdivided according to wavelength into IRA (k = 760 nm
to 1440 nm), IRB (k = 1440 nm to 3000 nm), and IRC
(k = 3000 nm to 1 mm). The depth of penetration into the skin
declines with increasing wavelength in the IR region.
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The formation of free radicals and ROS is of particular importance
for photocarcinogenesis and skin ageing. Because the topical application of sunscreens does not offer complete protection against UVdamage, antioxidants play a major role in the prevention and therapy of UV-induced skin ageing. The enzymatic and non-enzymatic
antioxidants of the skin are depleted by UV-induced oxidative
stress.54 In the skin, important non-enzymatic antioxidants are ascorbic acid, coenzyme Q 10, vitamin E, niacinamide and b-carotene.
Besides the topical application of antioxidants, endogenous
photoprotection through dietary micronutrients is becoming more
important, because the biggest part of a cumulative UV-dose is
obtained in everyday life without topically applied sunscreens.
Contrary to previous assumptions, at least 75% of a lifetime
UV-dose is attained after the age of 18.55 Topical application of
antioxidants and supplementation with micronutrients, such as
polyphenols and b-carotene, should be complementarily effected
with topical sunscreen.56
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However, no significant long-term studies are yet available on
topical antioxidants and supplementation of antioxidants proving
photoprotective properties.
Vitamins As other antioxidants, vitamin C is very instable when
exposed to air because of oxidation. Therefore, esterified derivatives are used for topical application. Besides its antioxidative
properties, vitamin C is essential for collagen biosynthesis because
it serves as a cofactor for two enzymes.57 In an animal model, vitamin C has shown to be photoprotective by decreasing UVBinduced erythema and the number of sunburn cells.58
The photoprotective effects of vitamin E have been shown in
numerous studies.59 Vitamin C and coenzyme Q10 synergistically
interact with vitamin E by reducing oxidized vitamin E, thus
enhancing the antioxidative properties of vitamin E.60
Niacinamide, also known as nicotinamide, is the amide of niacin (vitamin B3). The application of creams containing 4% and
5% niacinamide significantly reduced wrinkles and improved skin
elasticity (see Table 1).61,62 Although less potent than retinoids,
niacinamide is particularly suited for the periocular region because
of its non-irritating properties.
Carotenoids protect plants against oxidative stress and excess
light and exhibit an extended system of conjugated double bonds
essential for antioxidative properties.63 A meta-analysis showed
that oral supplementation with b-carotene protects against UVBinduced erythema. For significant protection against sunburn, a
minimum supplementation period of 10 weeks was noted.64 Carotenoids at high doses may have prooxidative effects. Endogenous
photoprotection attainable with b-carotene complies with sun
protection factor 4 at the most.64
Coenzyme Q10 Coenzyme Q10 (CoQ10, ubiquinone) is a fatsoluble antioxidant. In vitro CoQ10 reduced the UVA-induced
production of MMP in human fibroblasts.65 So far, only one study
showed wrinkle improvement using 1% CoQ10 cream for
5 months.66
Table 1 Overview of studies on topical antioxidants for the treatment of skin ageing
Authors
No.
patients
Study design
Study medication
Application
Duration
Clinical results
Bissett et al.
(2005)
50
Double-blind,
left-right
randomized
5% niacinamide vs.
vehicle
Twice daily to half of
the face and its
vehicle control to
the other half
12 weeks
After 12 weeks significant
reductions in
- fine lines and wrinkles
(P = 0.0005)
- hyperpigmented spots
(P = 0.006)
- red blotchiness (P = 0.03)
- skin sallowness (P = 0.0004)
(yellowing) compared with
vehicle control
- improvement of skin
elasticity compared with
vehicle control (P < 0.05)
Kawada et al.
(2008)
30
Randomized,
placebo-controlled,
split face study
4% niacinamide vs.
vehicle
Once daily to half of
the face and its
vehicle control to
the other half
8 weeks
After 8 weeks
- marked resp. moderate
improvement of wrinkles in
64% of the subjects with a
significant difference
compared with the control site
(P < 0.001)
- wrinkle grades were
significantly reduced
compared with control
(P < 0.001)
Humbert et al.
(2003)
20
Randomized
placebo-controlled,
double-blind study
Cream containing
5% vitamin C vs.
vehicle
Once daily on
low-neck and arms
6 months
- significant improvement, in
terms of the ‘global score’
(hydration, roughness,
suppleness, wrinkles and
laxity) compared with control
- highly significant increase in
the density of skin microrelief
- ultrastructural evidence of the
elastic tissue repair due to
reappearance of ‘composite’
elastic fibres in the papillary
dermis of vitamin c-treated
sides
- no changes of dermal collagen
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Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
Skin ageing
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Polyphenols
Polyphenols are secondary plant substances consisting of polycyclic aromatic compounds bonded with hydroxyl groups. Polyphenols dispose of both anti-inflammatory and antioxidant effects
and are capable of modulating several signalling cascades.
The photoprotective properties of green tea have been extensively investigated. Green tea is obtained from the leaves of the
plant camellia sinensis that mainly contain the polyphenols (-)epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3gallate (ECG) and (-)-epigallocatechin-3-gallate (EGCG), which
have antioxidant properties. Green tea offers potent anti-inflammatory, antioxidant and photoprotective qualities67,68 that may
prevent UV-induced skin changes.
In animal models, topical application or oral supplementation
with green tea polyphenols decreased UVA-induced roughness
and sagginess,69 attenuated UVB-induced erythema,70 and inhibited UVB-induced protein oxidation in the dermis. Besides, green
tea polyphenols were shown to diminish expression of MMPs
in vivo and in vitro.71
Topically administered polyphenols from green tea dosedependently inhibited UVB-induced CPD formation in the
human epidermis and dermis.72 Moreover, topically applied
green tea extracts prior to exposure to solar simulated radiation
reduced the number of histologically verifiable sunburn cells,
inhibited UV-induced erythema, maintained the depletion of
Langerhans cells,68 and inhibited UV-induced increase of epidermal thickness (Table 2).9 The UV-protective effects of green tea
polyphenols are presumably due to enhanced IL-12 mediated
DNA-repair.73
Silymarin, a flavonoid from milk thistle (Silybum marianum),
also reduced UVA ⁄ B-induced oxidative stress in animal models74
and attenuated photocarcinogenesis.75
Extracts of the fern polypodium leucotomos is endued with
strong antioxidant, anti-inflammatory and photoprotective properties.76–78 In humans, UV-induced skin changes were reduced by
oral supplementation with Polypodium leucotomos, which – prior
to exposure to solar simulated radiation – decreased UV-induced
erythema, the formation of sunburn cells, DNA-damage and
Table 2 Overview of clinical studies on photoprotective effects of green tea polyphenols and Polypodium leucotomos
Authors
No.
subjects
Study design
Study medication
Results
Elmets et al. (2001)
6
Areas of skin were treated
with an extract of green
tea or one of its
constituents. 30 min later,
the treated sites were
exposed to a 2 MED solar
simulated UVR
5% solution of green tea
polyphenols (GTPs)
Green tea polyphenols resulted in
a dose-dependent inhibition of
UV-induced erythema.
The (-)-epigallocatechin-3-gallate
(EGCG) and (-)-epicatechin-3gallate (ECG) polyphenolic
fractions were most efficient at
inhibiting erythema.
Histologically, application of
green tea polyphenols resulted in
a reduction of sunburn cells by
66% (P < 0.01) and reduced
depletion of Langerhans cells.
Green tea polyphenols also
reduced significantly the DNA
damage that formed after UV
radiation.
Middelkamp-Hup et al.
(2004)
9
Subjects were exposed to
varying doses of UV
radiation without and after
oral administration of
Polypodium leucotomos
(7.5 mg ⁄ kg)
Oral administration of
Polypodium leucotomos
(7.5 mg ⁄ kg)
A significant decrease in erythema
was found in PL-treated skin
(P < 0.01).
Histologically, PL-treated biopsy
specimens showed less sunburn
cells (P < 0.05), cyclobutane
pyrimidine dimers (P < 0.001),
proliferating epidermal cells
(P < 0.001), and dermal mast cell
infiltration (P < 0.05).
A trend towards Langerhans cell
preservation was seen.
10
Randomized, investigatorblinded, controlled study.
Subjects were exposed to
UVA without and after oral
administration of
Polypodium leucotomos
Oral administration of
Polypodium leucotomos
240 mg, 8 h and 2 h
before UVA exposure
A trend towards prevention of the
increase of the common deletion
in the Polypodium leucotomosgroup was seen.
Villa et al. (2010)
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dermal mast cell infiltration.76 Polypodium leucotomos may be
administered orally and topically.
Eicosapentaenoic acid
In human skin, topical application of eicosapentaenoic acid (EPA)
before UVA ⁄ B-exposure reduced epidermal thickening and inhibited UV-induced decrease of procollagen expression in vivo. In
intrinsically aged human skin, topical application of EPA increased
expression of ECM proteins (Table 3).79
Retinoids
The efficacy of topically applied tretinoin (all-trans-retinoic acid)
for the treatment of photoageing has been convincingly documented in several trials (Table 4). Significant effects were induced
by concentrations of 0.02% or higher, whereas a dose–response
relationship exists for both effectiveness and skin irritation. Significant improvements were found for fine wrinkling, skin roughness,
mottled hyperpigmentation, sallowness and the overall severity of
photodamage.80,81 Clinical improvement occurred after several
months of application; in addition, skin conditions continued to
improve with an application duration of at least 10–12 months.
Clinical results are reversible after cessation of therapy; thus, longterm treatment three to four times a week is recommended to
maintain clinical benefits. In the US, Tretinoin 0.05% is approved
by the FDA for the mitigation of fine wrinkles, mottled hyperpigmentation and tactile roughness of facial skin. Tazarotene, another
retinoid approved by the FDA to ameliorate some of the signs of
photoageing, is assumed to be as effective as tretinoin.82
Topical application of tretinoin prevents the UVB-induced
expression of MMPs through inhibition of the nuclear transcription factor AP-1 and obviates collagen degradation, which is
already initiated by low-dose UVB-irradiation.26
Histological effects differ depending on use duration. Initially,
increase of epidermal thickness and anchoring fibrils are observed.
Dermal effects in terms of neocollagenesis are not evident before
12 month application.83 According to the clinical effects described
above, histological examination shows an increase of collagen in
the papillary dermis accompanied by a decrease of solar elastosis.84
The melanin content also continues to decrease with the increasing
duration of therapy, correlating with improved mottled hyperpigmentation and solar lentigines.83 Evidence suggests that intrinsically aged skin may also benefit from the application of topical
retinoids.85
Hormones and growth factors
Study results on the cutaneous effects of hormone replacement
therapy are inconsistent.86 However, several studies have indicated
that hormone replacement therapy or the topical application of
oestrogen may ameliorate the effects of hormone deficiency. In
comparison to control groups, prevention of and improvements
in wrinkles have been documented87 as well as enhanced hydration88 and elasticity,88,89 accession of skin thickness88 and
increased collagen.8 Because of the well-documented side-effects,
risks and benefits should be diligently analysed before the inception of oestrogen supplementation.90
Table 3 Photoprotective effects and effects on extracellular matrix of eicosapentaenoic acid in human skin
Author
No.
subjects
Study design
Study medication
Results
Kim et al. (2006)
7 resp. 4
(A) Topical application of EPA
2% under occlusion vs.
vehicle once daily for 2 days
before UV-exposure (2 MED)
in volunteers (average age:
28 years)
(B) Topical application of EPA
2% vs. vehicle three times a
week for 2 weeks under
occlusion in volunteers
(average age: 76 years)
2% EPA in ethanolpolyethylene glycol (70 : 30)
vs. vehicle
(A) EPA inhibited UV-induced
epidermal thickening by
72 ± 12.6% (P < 0.05) compared
with vehicle.
EPA prevented UV-induced
decrease of procollagen
expression compared with vehicle.
Inhibition of UV-induced MMP-1
expression by 55 ± 13%
(P < 0.05) and MMP-9 expression
by 75 ± 7% (P < 0.05) compared
with vehicle.
Inhibition of UV-induced c-Jun
phosphorylation by 79 ± 11%
(P < 0.05) compared to vehicle.
Inhibition of UV-induced COX-2
expression by 76 ± 4% (P < 0.05)
compared with vehicle.
(B) EPA increased the expression
of procollagen by 218 ± 39%
(P < 0.05) compared with vehicle.
EPA increased the level of
tropoelastin and fibrillin-1 by
420 ± 53% (P < 0.05) compared
with vehicle.
JEADV 2011, 25, 873–884
ª 2011 The Authors
Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
Skin ageing
881
Table 4 Overview of studies on topical retinoids for treatment of skin ageing
Authors
No.
Study design
patients
Retinoid
Frequency of Duration
application
Clinical results
Randomized,
double-blind,
placebo-controlled
phase and an
additional 6-month
open-label phase
Tretinoin
microsphere gel
0.1%
Once daily on 6 months resp.
facial skin
12 months
At 6 months statistically significant
improvement relative to placebo in
- overall severity of photodamage
(P = 0.0003)
- investigator’s global assessment
of clinical response (P < 0.0001)
- fine wrinkling (P < 0.0001),
- mottled hyperpigmentation
(P = 0.0002)
- yellowing ⁄ sallowness
(P < 0.0001)
- lentigines (P = 0.0054)
Weiss et al.
(2006)
45
Kang et al.
(2005)
204
Randomized placebocontrolled
Tretinoin
emollient cream
0.05%
Once daily on 24 months
facial skin
Significantly greater improvement
relative to placebo in
- fine wrinkling
- coarse wrinkling
- mottled hyperpigmentation
- lentigines
- sallowness
- overall photodamage severity
- investigator’s global assessment
of clinical response (P < 0.05)
Phillips et al.
(2002)
563
24-week multicentre,
double-blind,
randomized, vehiclecontrolled intervention
study followed by a
28-week open-label
extension
Tazarotene
cream 0.1%
Once daily on 12 months
facial skin
Double-blind period:
Tazarotene resulted in a
significantly greater incidence of
patients achieving treatment
success (‡50% global
improvement) and at least a
1-grade improvement in fine
wrinkling, mottled
hyperpigmentation, lentigines,
elastosis, pore size, irregular
depigmentation, tactile roughness,
coarse wrinkling and the overall
integrated assessment of
photodamage (P < 0.01)
36
Randomized, doubleblind, vehiclecontrolled, left and
right arm comparison
study
0.4% retinol
(vitamin A) lotion
Up to three
times per
week on the
upper inner
portions of
the arms
Kafi et al.
2007)
Enhancing collagen production with topical oestradiol seems to
be restricted to intrinsically aged skin.91 Evidence suggests that
topical application of growth factors derived from human fibroblasts improves several features of photoaged skin.92
DNA repair enzymes
DNA-damage, such as CPDs, plays an essential role in photocarcinogenesis but also contributes to skin ageing. UVB-irradiated
human keratinocytes are involved in the induction of MMP-1
in dermal fibroblasts via paracrine mechanisms. MMP-1 induction was reduced when keratinocytes were treated with the
DNA-repair enzyme T4 endonuclease V (T4N5).93 The bacterial
DNA-incision repair enzyme T4N5 is encapsulated in liposomes
JEADV 2011, 25, 873–884
24 weeks
After 24 weeks significant
differences between retinol-treated
and vehicle-treated skin for
changes in fine wrinkling scores
[)1.64 (95% CI: )2.06 to )1.22)
vs. )0.08 (95% CI: )0.17 to 0.01);
P < 0.001]
for delivery into the living cells of the skin; here, the enzyme
recognizes CPDs and enhances dimer removal. The topical
application of a lotion containing T4N5 in patients with xeroderma pigmentosum lowered the incidence of non-melanoma
skin cancer.94
Photolyase is another DNA repair enzyme, which can be found
in numerous plants and animals but not in humans. Enzymatic
removal of CPDs requires exposure of the dimer-photolyase complex to photoreactivating light. The application of photolyase containing liposomes considerably reduces the amount of CPDs in
human skin. Besides, evidence suggests that topical application of
photolyase prevents UVB-induced immunosuppression, formation
of sunburn cells, erythema and tanning reactions.95 A sunscreen
ª 2011 The Authors
Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
Kohl et al.
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containing the DNA-repair enzyme photolyase is commercially
available.
Innovative approaches for photoprotection
DNA-oligonucleotides DNA-oligonucleotides (T-oligos) show
another possibility to enhance DNA-repair. DNA-oligonucleotides
homologous to the telomere 3-prime overhang sequence mimic a
telomere loop disruption and overhang exposure and initiate protective DNA-damage response. Treatment with t-oligos stimulates
melanogenesis and enhances DNA repair capacity. This displays
an innovative option for photoprotection, as both tanning and
increased DNA-repair rates are physiologically induced by UVexposure and DNA-damage to protect from further damage.96
Forskolin Tanning of the skin may also be induced by the topical application of forskolin, a cell permeable diterpene that stimulates adenylate cyclase activity. This enzyme is physiologically
activated after the binding of a-MSH to the melanocortin 1 receptor (MC1R), thus up-regulating cAMP-levels in melanocytes. As
effects of a-MSH are cAMP-mediated, the binding of a-MSH to
the MC1R may be obviated, and melanin production takes place
without any previous sun-exposure.
In animal models, pigmentation was compassed despite the
absence of a functional MC1R. Application of the cyclic AMP-agonist forskolin induced pigmentation in fair-skinned individuals
with defective MC1R who show sequence variants of the MC1Rgene.97 Besides, in vitro induction of pigmentation with forskolin
also showed enhanced DNA-repair, removing CPDs and 6,4photoproducts more efficiently.98
a-MSH analogues a-MSH, mediating UV-induced tanning, is
regarded as a cytoprotective agent. Synthesis of melanin may also
be stimulated by analogues of a-MSH that bind to melanocortin1-receptor on melanocytes. [Nle4-D-Phe7]-a-MSH (MT-1 or
Melanotan-1), a derivative of a-MSH with higher potency and
prolonged chemical stability than a-MSH, entails an explicit
increase of the melanin content in human skin in vivo when
injected subcutaneously. This effect was most pronounced in fair
subjects with a low minimal erythema dose threshold.99 However,
new findings indicate that a-MSH may actually increase mtDNA
damage because of increased oxidative stress within the frame of
elevated melanin synthesis.100
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ª 2011 The Authors
Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology