Abstract and Figures

Significance: Chronic exposure to environmental ultraviolet radiation (UVR) plays a key role in both photocarcinogenesis and induction of accelerated skin aging. Although the spatiotemporal consequences of UVR exposure for the composition and architecture of the dermal extracellular matrix (ECM) are well characterized, the pathogenesis of photoaging remains poorly defined. Given the compelling evidence for the role of reactive oxygen species (ROS) as mediators of photoaging, UVR-exposed human skin may be an accessible model system in which to characterize the role of oxidative damage in both internal and external tissues. Recent advances: Although the cell-mediated degradation of dermal components via UVR-induced expression of ECM proteases has long been identified as an integral part of the photoaging pathway, the relative importance and identity of cellular and extracellular photosensitizers (direct hit and bystanders models, respectively) in initiating this enzymatic activity is unclear. Recently, both age-related protein glycation and relative amino-acid composition have been identified as potential risk factors for photo-ionization and/or photo-sensitization. Here, we propose a selective multi-hit model of photoaging. Critical issues: Bioinformatic analyses can be employed to identify candidate UVR targets/photosensitizers, but the action of UVR on protein structure and/or ROS production should be verified experimentally. Crucially, in the case of biochemically active ECM components such as fibronectin and fibrillin, the downstream effects of photo-degradation on tissue homeostasis remain to be confirmed. Future directions: Both topical antioxidants and inhibitors of detrimental cell signaling may be effective in abrogating the effects of specific UVR-mediated protein degradation in the dermis.
Content may be subject to copyright.
Damage to Skin Extracellular Matrix Induced by UV Exposure
Rachel E.B. Watson,
Neil K. Gibbs,
Christopher E.M. Griffiths,
and Michael J. Sherratt
Significance: Chronic exposure to environmental ultraviolet radiation (UVR) plays a key role in both photo-
carcinogenesis and induction of accelerated skin aging. Although the spatiotemporal consequences of UVR
exposure for the composition and architecture of the dermal extracellular matrix (ECM) are well characterized,
the pathogenesis of photoaging remains poorly defined. Given the compelling evidence for the role of reactive
oxygen species (ROS) as mediators of photoaging, UVR-exposed human skin may be an accessible model system
in which to characterize the role of oxidative damage in both internal and external tissues. Recent Advances:
Although the cell-mediated degradation of dermal components via UVR-induced expression of ECM proteases
has long been identified as an integral part of the photoaging pathway, the relative importance and identity of
cellular and extracellular photosensitizers (direct hit and bystanders models, respectively) in initiating this
enzymatic activity is unclear. Recently, both age-related protein glycation and relative amino-acid composition
have been identified as potential risk factors for photo-ionization and/or photo-sensitization. Here, we propose
a selective multi-hit model of photoaging. Critical Issues: Bioinformatic analyses can be employed to identify
candidate UVR targets/photosensitizers, but the action of UVR on protein structure and/or ROS production
should be verified experimentally. Crucially, in the case of biochemically active ECM components such as
fibronectin and fibrillin, the downstream effects of photo-degradation on tissue homeostasis remain to be
confirmed. Future Directions: Both topical antioxidants and inhibitors of detrimental cell signaling may be
effective in abrogating the effects of specific UVR-mediated protein degradation in the dermis. Antioxid. Redox
Signal. 21, 1063–1077.
In humans, exposure to solar ultraviolet radiation (UVR)
has significant proven positive benefits, including the cu-
taneous production of vitamin D, and may potentially exert
cardio-protective effects via the synthesis of nitric oxide (37,
58). In contrast, excessive exposure to UVR is associated with
cataract formation in the lens; skin cancer; and premature skin
aging (2, 7, 170). This latter consequence of UVR exposure is
manifested primarily in the cell-poor, yet extracellular matrix
(ECM)-rich, dermis where altered tissue mechanical proper-
ties, resulting from structural and compositional remodeling,
are thought to drive the wrinkling that characterizes chroni-
cally photoaged skin (145, 146, 160, 170). Although many
potential effectors of UVR-mediated dermal matrix remodeling
have been identified, the relative importance of, and crucially
the interactions between, cellular and acellular pathways re-
mains poorly defined (119, 125, 149, 166). This review will
focus on the potential role of ECM proteins as both targets of
UVR and UVR sensitizers with a particular emphasis on the
importance of tissue architecture, protein diversity, and
amino-acid composition as key determinants of differential
tissue remodeling.
Skin Structure and Function
The skin is a complex organ that is composed of three
structurally and functionally disparate tissues. While the
deepest layer of the skin, the fat-rich hypodermis, may be
affected by chronic exposure to UVR, it is the dermis and
The Dermatology Centre, Salford Royal Hospital, Institute of Inflammation and Repair, The University of Manchester, Manchester
Academic Health Science Centre, Manchester, United Kingdom.
Centre for Tissue Injury and Repair, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health
Science Centre, Manchester, United Kingdom.
Volume 21, Number 7, 2014
ªMary Ann Liebert, Inc.
DOI: 10.1089/ars.2013.5653
outer epidermis that undergo the most pronounced acute and
chronic remodeling in response to UV irradiation (108, 170).
The epidermis, which varies in thickness between body sites
from less than 100 lm on the forearm and buttock to greater
than 600 lm on the heel, functions as a barrier to both water
loss and pathogen ingress (20, 86, 124). The epidermis is sub-
divided into several regions, beginning with the lowest single
cell layer, the stratum basale, of metabolically active stem cells
and their derived keratinocytes that lie above the dermis (83).
These basal keratinocytes terminally differentiate over a pe-
riod of 4 weeks to form the outermost stratum corneum, which
is composed of metabolically inactive and keratinized
squames that are embedded in a hydrophobic lipid matrix (86,
114). In addition to keratinocytes, the epidermis also contains
smaller numbers of pigment-forming melanocytes, immuno-
logically active Langerhans’ cells and sensory neurons, and
Merkel cells (81, 92).
The interface between the epidermis and the dermis, the
dermal–epidermal junction (DEJ), is thought to interact with
both basal keratinocytes in the epidermis and oxytalan fibers
(elements of the terminal elastic fiber network) on the dermal
side (60, 163). Central to the DEJ is a specialized basement
membrane, rich in laminin-332 and collagen IV, that is char-
acterized by a6b4 integrin-mediated keratinocyte attachments
and by collagen VII anchoring fibrils on the epidermal and
dermal sides, respectively (17, 26, 142). In addition to these
molecular attachments, the topology of the DEJ, which in
young, photoprotected Caucasian skin is characterized by
intercalating dermal and epidermal papillae, may play an
important role in dermal-epidermal attachment and shear-
stress resistance (78, 152). However, most of the mechanical
characteristics of skin are thought to be conferred by the
supporting dermis.
The dermis, which may vary in thickness from 1 mm on the
forearm to 2 mm on the thigh, contains hair follicles, eccrine
and apocrine sweat glands, blood and lymphatic capillaries,
sensory neurons, and a diverse cellular population of resident
fibroblasts and immune cells (73, 76, 82, 84, 115, 126, 133).
Despite this compositional diversity with regard to sub-
structures and cell types, the tissue itself is composed pre-
dominantly of highly stable (half lives of years or decades)
ECM proteins that continue to function largely in the absence
of the damage detection and repair mechanisms which protect
short-lived proteins (half lives of hours or days) within the
intracellular environment (45, 63, 129, 156). Many of these
proteins are thought to perform key mechanical roles: fibrillar
collagens I, III, and V, for example, resist tensile forces; while
negatively charged and, hence, hydrophilic proteoglycans
such as versican and the glycosaminoglycan hyaluronic acid
resist compressive forces. The dermal elastic fiber system,
which is composed primarily of elastin and fibrillin microfi-
brils, confers passive recoil (18, 64, 71). In addition to these
major structural proteins, many ECM components perform
crucial biochemical roles by mediating: matrix–matrix inter-
actions and, hence, assembly (for example, the small leucine-
rich proteoglycans); cell-matrix interactions (as controlled
primarily by adhesive glycoproteins and soluble cytokines);
and matrix homeostasis (as a consequence of matrix me-
talloproteinase [MMP]-driven degradation and inhibition and
transforming growth factor b[TGFb] sequestration) (3, 44, 50,
53, 87, 122). In contrast to internal organs, these molecules and
the cellular components of the dermis and epidermis are
required to resist exposure to potentially damaging electro-
magnetic radiation.
Biological and Clinical Consequences of Exposure
to Ultraviolet Radiation
UVR, which forms only a small component of solar radia-
tion, is conventionally split into high-energy UVC (wave-
length 100–280 nm) and lower-energy UVB (280–315 nm) and
UVA (315–400 nm) wavebands (Fig. 1a). However, while be-
ing biologically highly damaging, UVC radiation is absorbed
by stratospheric ozone and is not, therefore, a component of
terrestrial solar radiation (52). As a consequence, human skin
at the Earth’s surface is exposed to less energetic UVB and
UVA radiation. UVB radiation, which comprises only 5% of
terrestrial UVR, penetrates no further than the papillary der-
mis whilst UVA radiation, which comprises the remaining
95%, may penetrate the whole dermis to reach the sub-
cutaneous fat (4, 31) (Fig. 1b). This exposure has both short-
and long-term impacts on human health.
Positive effects of UVR
Humans, in common with other primates, obtain vitamin D
either through dietary sources or through the UVB/heat-
induced conversion of cutaneous 7-dehydrocholesterol to pre-
vitamin D
and then vitamin D
in the skin (58). However,
lack of sunlight exposure, particularly at higher latitudes,
when compounded by a diet that is poor in vitamin D, may
contribute to longer-term deficiencies which not only impact
on the structure and function of the growing and mature
skeleton but have also been linked to the development of
disparate forms of cancer, multiple sclerosis, and cardiovas-
cular disease (51, 58, 175). In addition to the beneficial effects
of UVB-mediated vitamin D synthesis, UVA radiation may
liberate bound nitric oxide, which, in turn, may exert a pow-
erful cardioprotective effect (37, 113). Remarkably, when
other known risk and protective factors are accounted for,
mortality within the United Kingdom correlates linearly with
latitude (79). These beneficial effects, both well established
and putative, should be balanced against the profound neg-
ative impacts of excessive UVR exposure.
Negative effects of UVR
In the short term, UVR may induce acute clinical effects,
including skin inflammation (in which vasodilation contrib-
utes to erythema or skin reddening) and immunosuppression
[for in-depth reviews, see Refs. (22, 88)]. Chronically, UVR-
induced epidermal deoxyribonucleic acid (DNA) damage and
consequent mutation of tumor suppressors and oncogenes
initiates nonmelanoma skin cancers and is associated with
melanoma (15, 59, 104, 174). As a consequence of the adverse
effects on health of both low (vitamin D deficiency and re-
duced NO-mediated cardio-protection) and high (principally
skin cancer) UVR exposure, there is ongoing debate on the
risk-benefit relationship of UVR exposure, in relation to the
quantification of optimal UVR exposure for cutaneous vita-
min D synthesis and public health advice on the use of topical
UV filters (sunscreens) (48, 49, 89, 173). Regardless of the
outcomes of this debate, there is a consensus that chronic
exposure to UVR (photoexposure) induces profound changes
in skin structure, which, in turn, manifest as apparent skin
aging (photoaging) (105, 170). Establishing the main causative
mechanisms of photoaging would impact not only com-
mercially important cosmetic concerns but also attempts to
understand the link between photoaging and skin cancer
(170). In addition, chronically UVR-exposed skin provides an
important human tissue in which the role that oxidative
damage may play in driving systemic pan-species aging is
studied (45).
Skin aging and photoaging
Although there is some commonality between the ap-
pearance of chronological (also known as intrinsic) and UVR-
induced (extrinsic) skin aging, both the severity and speed of
onset of outward manifestations such as wrinkles and tissue
laxity and the nature of the underlying structural remodeling
differ (14, 35, 129). Specifically, intrinsically aged skin, which
is typically evident only at an older age (from the eighth de-
cade onward), remains unblemished but is characterized
macroscopically and functionally by the development of fine
wrinkles and by reduced mechanical compliance and resi-
lience (ability to recoil) (35, 36, 99). Microscopically, both the
epidermis and dermis undergo atrophy, the DEJ becomes less
convoluted, Langerhans’ cells and fibroblast populations are
depleted, and the dermal ECM loses structural oligosaccha-
rides (proteoglycans and hyaluronic acid) and fibrillar colla-
gens (35, 38, 46, 47, 68, 109, 121, 152). Where present, the
effects of extrinsic aging are superimposed on this back-
ground of intrinsic aging.
When rigidly interpreted, the term extrinsic aging refers to
tissue remodeling that may be induced by multiple external
factors, including both UVR exposure and smoking; in prac-
tice, however, the terms photoaged and extrinsically aged
skin are often used synonymously (102, 105). Clinically, se-
verely photoaged skin appears deeply wrinkled and unevenly
pigmented and is both less compliant and less resilient than
photoprotected skin (1, 36, 77, 160, 170). This lack of resilience
is particularly striking given that the photoaged dermis is
characterized not only by the loss of fibrillar collagens and
collagen VII-containing anchoring fibrils at the DEJ but also
by the gain of oligosaccharides (proteoglycans and hyaluronic
acid) and nominally resilient components of the elastic fiber
system (12, 13, 26, 35, 97, 147). Crucially, however, the normal
hierarchy of this latter system (elastin-rich elastic and elaunin
fibers in the reticular dermis and fibrillin-rich oxytalan fibers
in the papillary dermis) is lost in photoaged skin (105). The
process begins with the specific loss of oxytalan fibers (and
their associated components such as fibrillin and fibrulin-5)
from the papillary dermis (65, 162, 163) and ends with the
apparent deposition of elastin and fibrillin-containing mate-
rial (termed solar elastosis) in the reticular dermis (12, 97, 105).
In contrast to intrinsic aging, which is characterized by
the gradual loss of ECM components from the dermis,
any putative photoaging mechanisms should account for
the differential spatiotemporal remodeling of specific ECM
Molecular Targets of UVR
An understanding of photochemistry is based on the
Grotthuss—Draper law which states that ‘‘photon energy
must be absorbed in order to have a subsequent reaction’’
(166). This absorption may directly affect the structure of the
FIG. 1. SSR is primarily composed of penetrating, yet
low-energy, UVA wavelengths. (a) Normalized spectral
outputs of broadband UVB, SSR, and filtered SSR (UVA)
sources. The spectral output of SSR (emitted by a WG320
filtered xenon arc lamp) is composed of UVA and UVB ra-
diation (95.0% and 5.0%, respectively). The effects of UVA
radiation can be investigated by further filtration (WG345) to
remove the majority of the UVB component (UVA: 99.6%,
UVB: 0.4%). Previously, we have characterized the effects of
irradiation with a broadband UVB source (Philips TL-12;
44.3% UVA, 55.3% UVB, and 0.4% UVC) on the structure of
purified collagen I, fibronectin, and fibrillin microfibrils,
while other groups have examined the effects of UVC or
UVC-containing radiation (e.g. germicidal at 254 nm) on the
structure and function of fibrillar collagen (131, 149). (b)
Relative penetration of UVC, UVB, and UVA wavebands
into human skin (in this biopsy from photoprotected buttock,
the epidermis is stained with nuclear fast red and the lower
dermis is demarcated by immunohistochemical staining for
intact fibrillin microfibrils). In most areas of the body, UVC
radiation is unlikely to penetrate into the dermis. In contrast,
solar UVB radiation can influence the structure of the pap-
illary dermis, while solar UVA radiation penetrates
the whole depth of the dermis to reach the underlying
subcutaneous tissue [adapted from Askew (4)]. SSR, solar-
simulated radiation.
target molecule or generate reactive oxygen species (ROS)
(via photosensitization), which, in turn, may damage the
same target molecule or other molecular components (111).
Alternatively, ROS may affect tissue homeostasis via their
influence on cell signaling and phenotype (119). In order,
therefore, to understand the mechanisms that drive photoa-
ging of human skin, it is necessary to identify which molecules
act as UVR absorbers (chromophores), where these molecules
are located (in cellular or intracellular compartments), and
what the downstream molecular consequences of this ab-
sorption are.
UVR chromophores in human skin
By definition, the term chromophore refers solely to the
radiation-absorbing region of a molecule; in practice, how-
ever, UVR-absorbing biological polymers such as DNA are
often referred to as UV chromophores (172). In the case of
DNA, the absorption of UVR produces highly mutagenic
photolesions, such as cyclopyrimidine dimers, in tumor sup-
pressors or oncogenes and results in the initiation of skin
cancer (30). Protection against such events is afforded by
melanin, which is most abundant and most readily inducible
in skin phototypes V and VI (127, 172). Other small molecules
that act as UVR chromophores (and in some cases, as photo-
sensitizers) include urocanic acid, the porphyrins and flavins,
vitamin K and B
derivatives, bilirubin, NAD(P)H, and ad-
vanced glycation end products. The reader is referred to ex-
cellent reviews by Young and by Wondrak et al. for detailed
discussions of the identity of these skin chromophores and
their complex absorption characteristics and resultant pho-
tochemistry (166, 172). However, while the most abundant
molecules in human skin are the structural proteins of the
dermis and it is these same components that undergo pro-
found remodeling in UVR-exposed tissue, the role of ECM
proteins as UVR chromophores and sensitizers remains less
well defined.
Proteins as UVR chromophores
After absorbing photon energy, chromophores within
proteins may enter a short-lived, singlet excited state, result-
ing in direct perturbations to molecular structure (111). Al-
ternatively, this singlet state can undergo intersystem,
crossing to a longer lived triplet state that has the potential to
act as an intra-molecular photosensitizer. Such photosensi-
tizers can, in turn, undergo either type I (electron transfer) or
type II (energy transfer) reactions to form radical species (e.g.,
superoxide radical anion) or singlet O
) (29, 42). Com-
pelling experimental evidence for a link between photo-
damage and protein oxidation was first presented by Sander
et al., who identified a dose-dependent accumulation of
oxidation-induced protein carbonyls in the acutely UVR-
exposed papillary dermis (125). However, the susceptibility of
specific ECM dermal proteins to UVR-mediated degradation
will be determined, in part, by their chromophore content that
may be nonprogrammed (due to post-translational modifi-
cation with other chromophores, including photosensitizers
such as porphyrins, riboflavin, and glycation-derived cross-
links) or programmed (as a consequence of amino-acid com-
position and macro-molecular structure) (111, 150, 166).
There is increasing experimental and theoretical support
for the role played by post-translationally modified proteins
in mediating UVR-induced DNA damage and, hence, cellular
phenotype (165, 167–169). In addition to these intracellular
effects, post-translational modification of ECM proteins such
as fibrillar collagens and elastin (via targeted lysyl oxidase
[LOX]-driven cross-links or age and diabetes-induced glyca-
tion) may influence the mechanical behavior of tissues, in-
cluding skin, lungs, and blood vessels and, hence, cellular
phenotypes (via mechanotransduction pathways) (6, 62, 80,
143, 144, 164). The major structural proteins such as fibrillar
collagens and elastin are not, however, the only targets of
glycation. Less abundant, yet still biologically important ECM
components, including adhesive glycoproteins, elastic fiber-
associated proteins, and basement membrane components,
may also react with glucose (5, 66, 148). The relative suscep-
tibility of different ECM proteins to glycation (and, hence, to
UVR-mediated damage via photosensitization) is likely to
depend on: (i) the availability of free Lys and Arg residues
after enzymatic cross-linking and (ii) cumulative absorbed
UVR dose, as determined by protein architecture within the
dermis, exposure to both glucose and UVR (dependent, in
part, on molecular longevity), and the functional form of the
protein. For example, while both collagen I and tropoelastin
are long lived in human skin, and hence have ample oppor-
tunity to become glycated, their functional macromolecular
structures in mature tissues (monomers assembled into large-
diameter dense fibrils and fibers) ensure that in most cases the
internal constituent proteins of collagen fibrils and elastic fi-
bers will be protected from interstitial glucose and hence from
glycation (71, 120, 140, 155).
Differential glycation of protein species may result from
differences in their free Lys composition. Both the a1 chain of
collagen I (Swiss Prot Accession: Q9UML6) and the precursor
of elastin (tropoelastin: Q6P0L4), for example, contain similar
numbers of Lys residues (38/and 44/1000 residues, respec-
tively) but after LOX-driven cross-linking a1(I), collagen still
contains 25–26 free Lys residues per 1000 compared with only
5–6 for tropoelastin (6). Finally, ECM proteins are unevenly
distributed within the dermis and as a consequence, fibrillin-
microfibril-associated proteins, which form arborizing (and,
hence, low density) oxytalan fibers in the papillary dermis,
could be key targets of glycation-mediated photosensitization
Although post-translational modifications, macro-molecular
structure, longevity, and architecture may play important
roles in mediating protein susceptibility to UVR, a neglected
area of study is the influence of relative amino-acid compo-
sition on the ability of individual protein species to act as
Amino-acid composition as a determinant
of protein chromophore load
Individual proteins differ not only in their primary struc-
tures (amino-acid sequences) but also in their relative amino-
acid compositions. Of the 20 amino-acid residues that
comprise human proteins, Leu is the most common and Trp is
the least common (*10% and 1%, respectively, of the 19,889
characterized human proteins documented in the Swiss Prot
database: Fig. 2). Furthermore, not all residues absorb the
UVR wavelengths that are present in sunlight; UVB radiation
is absorbed by Cys, Trp, Tyr, and His residues only (10, 34,
111). Of these residues, the susceptibility of Cys, Trp, and Tyr
to photochemical modification is well established and from
their absorption spectra, we can conclude that Tyr, and to a
much greater extent Trp and Cystine (disulfide bonded Cys),
are likely to be the key mediators of photochemical UVA-
mediated damage to dermal proteins in vivo (27). Therefore,
proteins that are rich in these residues and in Met may be key
targets of photodegradation and indirect
photo-oxidation [see Pattison et al. (111) for an in-depth
review]. However, these amino-acid residues are under-
represented in human proteins (Fig. 2), and we have previ-
ously proposed that relative amino-acid composition may be
used to identify dermal ECM proteins or protein families
which are either UVR/ROS resistant (primarily collagens) or
labile (elastic fiber-associated proteins—with the exception
of elastin itself ) (131, 149). By plotting the concentration of
sulfur-containing (Cys and Met) against aromatic (Trp and
Tyr) amino-acid residues, we can establish that this predicted
differential UVR/ROS susceptibility is also evident when
these groups (collagens and elastic fiber components) are
compared with the entire human proteome (Fig. 3).
Experimental evidence for the degradation
of collagens and elastin by UVR
The predicted resistance of fibrillar collagens to UVR can be
tested experimentally. Fibrillar collagens (and in particular,
collagen I) are the most abundant components of human skin
and as a consequence, their susceptibility to in vitro UVR has
been extensively studied. From an initial reading of the liter-
ature, it appears that fibrillar collagens are, in fact, UVR-labile.
Reported UVR-induced structural changes include modifica-
tions to Tyr and Phe residues, altered electrophoretic mobility,
and fragmentation of collagen monomers (23, 57, 61, 67, 94,
96, 98, 116). These structural changes may have functional
consequences impacting collagen mechanical properties,
resistance to protease digestion, thermal stability, triple helix
formation, and fibrillogenesis (24, 25, 28, 43, 91, 93, 95, 98,
116, 135, 136). However, each of these studies employed
UVR sources that emitted some short wavelength UVC ra-
diation (Table 1). Such high energy sources can induce skin
reddening (minimal erythemal dose [MED]) at doses of just
0.01 J/cm
(32). In contrast, the MEDs for lower-energy UVB
higher: 0.05 and 56.5 J/cm
compare the potential biological impact of UVR doses
emitted from the disparate sources used by researchers over
a time span of nearly five decades, we have, where possible,
expressed these UVR doses as MEDs. (55, 74, 85, 131, 159).
From this analysis, it is clear that nonphysiological UVR
wavelengths, and in many cases doses (approximately four
inducing profound structural and functional remodeling of
fibrillar collagens in vitro. However, when physiologically
attainable wavelengths and doses are used, the evidence for
UVR-induced collagen denaturation is much less compelling
(Table 2). UVA/UVB-rich radiation sources have a minimal
effect on collagen structure and function even when the
doses employed are more than two orders of magnitude
greater than the MEDs of the respective wavebands (67, 90,
91, 131).
In addition to the fibrillar collagens that confer tensile
strength, the mechanical properties of the dermis are also
determined by a complex network of elastin-rich elastic fibers.
Although otherwise biochemically and structurally dissimilar
to the collagen triple helix, the repeating domain structure
of elastin is also largely devoid of UVA-absorbing and
ROS-sensitive Cys, Trp, Tyr, and Met residues (69). When
compared with the extensive literature on UVR/collagen in-
teractions, the effects of UVR on the structure of elastin are
poorly defined, although it has been demonstrated that elas-
tin-derived peptides undergo structural modification after
exposure to very high-dose UVC radiation (300 MED) (137,
138). Therefore, from the experimental evidence, it appears
that the major long-lived structural proteins of the ECM are
likely to be protected from the action of UVR and ROS by their
amino-acid composition.
UVR-mediated degradation of ECM glycoproteins
In addition to an extensive network of collagen fibrils, elastic
fibers, and hydrophilic proteoglycans, the ECM contains
FIG. 2. UVR-susceptible and oxidation-sensitive amino
residues are under-represented in human proteins. In
comparison to the relatively abundant Leu and Ser residues,
human proteins contain fewer UVA/UVB and oxidation-
sensitive amino acids (indicated in black). UVR, ultraviolet
abundant structural glycoproteins that play dynamic roles in
organizing and maintaining matrix structure (75). Foremost
among these glycoproteins is fibronectin, a ubiquitous ECM
component, which is present as both high molecular mass
dimers in plasma and functional fibrils in the matrix (101).
These fibrils contain binding sites for matrix components,
including collagens, heparin, and fibronectin itself and cru-
cially also for cell-membrane bound integrins (134). It is via
these RGD (Arg-Gly-Asp) site/integrin interactions that fi-
bronectin exerts influence over cell migration, morphology,
and oncogenic transformation (75, 151). Compared with both
collagen I and tropoelastin, fibronectin is relatively rich in the
UVA chromophores Cys, Trp, and Tyr (0.3%, 2.2%, and 8.5%
respectively). Hence, fibronectin may be a key target of
UVR-mediated degradation in vivo. However, while there is
evidence that human dermal fibroblasts respond to UVA ex-
posure (both in vitro and in vivo) by synthesizing fibronectin,
descriptions of the consequences of UVR exposure on fibro-
nectin structure are, to our knowledge, limited to a study
which we published in 2010 (11, 128, 131). We demonstrated
using both polyacrylamide gel electrophoresis and atomic
force microscopy (AFM) that fibronectin could be induced to
aggregate by exposure to relatively low doses of broadband
UVB radiation. In addition, we showed by using AFM that
exposure to broadband UVB radiation altered the molecular
dimensions of discrete fibronectin dimers. Such structural
remodeling (with its attendant risk of cytotoxic amyloid for-
mation) is a common response of diverse polypeptide chains
to oxidation and/or UV irradiation both in vitro and in tissues
such as the lens (100, 141, 158).
Since even small changes in fibronectin structure, induced
by adsorption to hydrophilic or hydrophobic surfaces, for
example, can affect cell adhesion, UVR-mediated fibronectin
denaturation in vivo has, therefore, the potential to profoundly
affect cell phenotype and hence tissue homeostasis (72, 130,
132). We should note, however, that these broadband UVB
radiation-induced changes in fibronectin only became evident
at multiple MEDs (4–10 times) but that this was not the case
for key components of the elastic fiber system such as fibrillin
microfibrils. These assemblies are both UV-chromophore rich
(fibrillin-1 16.4% Cys, Trp, and Tyr content) and highly UVR
Elastic fiber-associated proteins as key targets of UVR
The potential role of cell-derived ECM proteases in medi-
ating dermal remodeling in photo-exposed skin is well es-
tablished. UVR exposure not only up-regulates the expression
of MMPs-1, -2, -3, -7, -9, and -12 (21, 39, 41, 123) but also
promotes a pro-oxidative environment in human skin. In
turn, this protease and ROS-rich environment may cause the
activation of newly synthesized and sequestered MMPs by
enzymatic or oxidative pathways, both of which operate on
a common cysteine switch (8, 19, 117). Collectively, how-
ever, these enzymes are capable of degrading most dermal
ECM components, including fibrillar collagens, elastic fiber
FIG. 3. Elastic fiber-associated
proteins are enriched in UVR and
oxidation-susceptible amino acids.
The majority of human proteins
(19,889 proteins described in the
Swiss Prot database) contain be-
tween 3% and 5% Cys +Met or
Trp +Tyr residues. In contrast, (i)
many elastic fiber proteins, includ-
ing both the heavily disulfide-
bonded calcium-binding epidermal
growth factor-like domain contain-
ing fibrillins, fibulins, and LTBPs
and the biochemically dissimilar
lysyl oxidases (LOX and LOXLs)
and MAGPs, are enriched in Cys,
Met, Trp, or Tyr residues and (ii)
common fibrillar, anchoring, and
network-forming collagens are lar-
gely devoid of these residues.
MAGPs, microfibril-associated gly-
coproteins; LTBPs, latent trans-
forming growth factor b-binding
Table 1. Fibrillar Collagens Are Degraded by High-Dose UVC Radiation
UVR waveband/source J/cm
MED Extraction method/tissue source Structural/functional effect Study
4W–Sankyo Electric Co. ND ND Acid soluble from calf skin Loss of structure/reduced fibril formation Miyata et al. (98)
Varian Spectro-polarimeter ND ND Chick tendon fibroblasts Fragmentation of monomeric collagen Hayashi et al. (57)
Eiko Co. low pressure Hg lamp ND ND Human placenta Fragmentation of monomeric collagen Kato et al. (67)
Philips TUV 6W lamp ND ND Acid soluble from rat tail Fragmentation of monomeric collagen Miles et al. (96)
UVP CL-1000 cross-linker ND ND Acid soluble from rat tail tendon Increased stiffness/protease resistance Cornwell et al. (25)
Conrad-Hanovia, Inc. filtered
Xenon lamp 901C-0011
1 100 Acid soluble from rat tail tendon Reduced fibril formation Fujimori et al. (43)
UV Products shortwave UVG-11 lamp 5.3 530 Acid soluble Reduced fibril formation Menter et al. (91)
Philips TUV-30 Hg lamp 16 1600 Acid soluble from rat tail tendon Modification of Tyr and Phe residues Sionkowaska and
Kaminska (135)
Philips TUV-30 mercury lamp 16 1600 Acid soluble from rat tail tendon Loss of structure Metreveli et al. (94)
Philips TUV-30 Hg lamp 32 3200 Acid soluble from rat tail tendon Reduced thermal stability Sionkowska and
Kaminska (136)
UV Products Model R-52 Grid Lamp 102 10,200 Acid soluble from rat tail tendon Fragmentation of monomeric collagen Jariashvili et al. (61)
Spectroline Corp. R-51A lamp, 105 10,500 Acid soluble from rat tail Loss of structure/altered mechanical
Rabotyagova et al. (116)
Conrad-Hanovia, Inc. filtered
Xenon lamp 901C-0011
21.5 430 Acid soluble from rat tail tendon Reduced fibril formation Fujimori et al. (43)
DRT-230 High pressure Hg lamp ND ND Acid soluble from rat tail tendon Reduced thermal stability Metreveli et al. (95)
DRT-230 High pressure Hg lamp 9 900 (UVC) Rat tail tendon Reduced thermal stability Metreveli et al. (93)
Hanovia UVS 220A lamp 148 (UVB) 2960 (UVB) Salt soluble from calf skin Loss of structure Cooper and Davidson (23)
Hanovia UVS 220A lamp 148 (UVB) 2960 (UVB) Salt and acid soluble from calf skin Impaired gelatin to triple helix transition Cooper and Davidson (24)
Hanovia UVS 220A lamp 148 (UVB) 2960 (UVB) Salt and acid soluble from calf skin Impaired gelatin to triple helix transition Davidson and Cooper (28)
The structure and function (both mechanical and biochemical) of purified fibrillar collagen (predominantly collagen I) is profoundly disrupted by exposure to UVC-containing radiation sources
(emitting primarily 254 nm) and delivering doses many orders of magnitude higher than the predicted MED for UVC-exposed human skin. UVR wavebands: UVC 100–280 nm (predominantly 254 nm);
UVB 280–315 nm; UVA 315–400 nm.
MED, minimal erythemal dose; UVR, ultraviolet radiation; ND, not determined.
constituents, proteoglycans, adhesive glycoproteins, and DEJ
basement membrane components (3, 19, 110). Therefore, it is
difficult to reconcile the concept of cell-derived ECM proteases
as the sole mediators of matrix degradation with the complex
spatial, compositional, and temporal ECM remodeling that
characterizes chronically UV-exposed skin. Hence, while the
suggestion that ECM components may be targets of UVR is
not new, we have additionally proposed that elastic fiber-
associated components in particular, by virtue of their high
UVR-chromophore content, may be important mediators of
dermal remodeling in photoaged tissue (28, 90, 131, 149, 166).
We have demonstrated experimentally that even sub-MED
doses of broadband UVB radiation (20 mJ/cm
: 0.4 MED) are
capable of inducing profound changes in fibrillin microfibril
morphology (131). Similar changes in molecular structure,
when arising as a consequence of inherited mutations in the
fibrillin-1 gene, are associated with the life-threatening vas-
cular pathologies that characterize the heritable connective
tissue disorder Marfan Syndrome (70, 118). Hence, the
susceptibility of these disulfide-bonded microfibrils (and po-
tentially of the structurally related fibulins and latent trans-
forming growth factor bbinding proteins [LTBPs]) to
environmentally relevant doses of UVR provides a potentially
selective mechanism for (i) the early photochemical degra-
dation of oxytalan fibers (fibrillin-rich microfibril bundles) in
the papillary dermis and (ii) the subsequent remodeling of the
elastic fiber system in the reticular dermis as a consequence of
microfibril exposure to penetrating UVA radiation. In this
latter case, photochemical degradation of fibrillin microfibrils
is likely to be the triggering event that leads to aberrant TGFb
signaling, the up-regulation of both MMP and tropoelastin
synthesis, the subsequent dysregulation of elastogenesis, and,
Table 2. Fibrillar Collagens Are Largely Resistant to Low-Dose UVA and UVB Radiation
UVR waveband/source J/cm
Extraction method/
tissue source Structural/functional effect Study
Toshiba 20W black
light lamp
40 0.7 Collagen IV No effect on electrophoretic
Kato et al. (67)
Schott WG 345
filtered Xenon arc
623 11 Acid soluble Minimal effect on fibril
Menter et al. (91)
FS-36 filtered 3.9 34 Acid soluble
from calf skin
Increased protease
Menter et al. (90)
Xenon arc 973 262 Acid soluble Minimal effect on fibril
Menter et al. (91)
Philips TL-12 0.5 (UVB) 10 (UVB) Acid soluble
collagen I
No effect on electrophoretic
Sherratt et al. (131)
UVR, which is low dose and/or devoid of nonphysiological wavelengths, has no (or very limited) effect on fibrillar collagen structure,
fibrillogenesis, or protease susceptibility. UVR doses are expressed relative to approximate MED equivalents as calculated for the various UV
sources using published skin phototest data (55, 74, 85, 131, 159). All collagens are assumed to be primarily fibrillar (collagen I, III, or V)
unless otherwise stated. UVR wavebands: UVC 100–280 nm (predominantly 254 nm); UVB 280–315 nm; UVA 315–400 nm; SSR 280–400 nm.
SSR, solar-simulated radiation.
FIG. 4. The direct hit and
bystander models of photo-
aging. In the direct hit model,
UVR interacts with intracellular
photosensitizers and induces
the expression of MMPs,
which, in turn, degrade the
ECM. In the bystander model,
the photosensitizer is thought
to be located extracellularly and
some ROS-mediated ECM
degradation is postulated, but
MMPs remain key mediators of
matrix degradation (166). ECM,
extracellular matrix; MMP,
matrix metalloproteinase; ROS,
reactive oxygen species. To see
this illustration in color, the
reader is referred to the web
version of this article at
hence, the deposition of elastotic material (solar elastosis) (16,
33, 106, 107, 171).
Mechanisms of Photoaging
The accumulating theoretical and experimental evidence
for the role played by specific protein families in mediating
downstream tissue remodeling leads us to propose a new
model of photoaging that combines and extends the two ex-
isting models (direct hit and bystander) as defined by Won-
drak et al. (166) (Fig. 4).
Direct hit and bystander models of photoaging
Although ECM remodeling is the key structural change in
photoaged skin, existing models of photoaging have focused
primarily on the influence of UVR on cell behavior. In the
direct hit model, UVR is absorbed by intracellular photosen-
sitizers to produce H
or singlet oxygen, which act via
cellular signaling pathways involving the inhibition of
protein-tyrosine phosphatase-j, activation of epidermal
growth factor receptor, stimulation of mitogen-activated and
c-Jun amino terminal kinases, and subsequent transcription of
nuclear transcription complex AP-1 or the expression of in-
terleukins-1a,-1b, and -6 to up-regulate the expression of
ECM-degrading MMPs [for detailed reviews, see Refs. (119,
153, 170)]. By contrast, in the bystander model, the photo-
sensitizer (which may be a glycated protein) is located in the
ECM and liberates ROS, which both degrades ECM proteins
directly and promotes MMP expression and activity (166).
Since these models are not mutually exclusive and in their
present form cannot explain the specific degradation of key
elastic fiber components (fibrillin-1 and fibulin-5) that char-
acterize early photoaging, we propose a new combined model
of photoaging: the selective multi-hit model, in which UVR-
chromophore-rich cellular and extracellular photosensitizers
mediate both direct and bystander effects (Fig. 5) (65, 131, 149,
Selective multi-hit model
Identifying the key intracellular proteins that act as photo-
sensitizers will require a combination of detailed bioinformatic
analysis and experimental investigation. We can, however,
begin to classify extracellular proteins as potential photosensi-
tizers according to their amino-acid composition, susceptibility
to glycation, location in the dermis, and macro-molecular
structure. Hence, fibrillar collagens that are Cys-, Trp-, and Tyr-
poor, resistant to glycation in their fibrillar form, diffusely
distributed throughout the dermis, and present as dense fibrils
and fibril bundles are unlikely to be targets for UVR (139, 157).
Instead, UVR-upregulated MMPs (-1, -2, -3, and -9) may be the
main mediators of fibrillar collagen (I, III, and V) degradation
(19, 39, 41). Nonfibrillar collagens such as microfibrillar colla-
gen VI are also UV-chromophore poor and their predicted lack
of UVR susceptibility, combined with the absence of known
proteases for the assembled form, may underlie the resistance
of collagen VI to photoaging in vivo (103, 154, 161).
In contrast to the UVR-resistant collagens, the proteoglycan
fibromodulin (which modulates collagen fibrillogenesis), the
adhesive glycoproteins thrombospondin-1 and -2 and vi-
tronectin, the basement membrane components (laminin-332,
laminin-311) and perlecan (which will be exposed to relatively
high UVB doses at the DEJ), and crucially, the microfibril-
associated components of the elastic fiber system are potential
UVR chromophores and photosensitizers (4, 9, 54, 131). These
FIG. 5. Selective multi-hit model of photoaging. Incident UVR radiation will interact with both cellular and extracellular
protein chromophores and in doing so, will liberate both ROS and induce expression of MMPs. Oxytalan fibers in the
papillary dermis (which contain fibrillin and potentially fibulins and LTBPs) are likely to be extracellular photosensitizers
whose partial degradation may have profound effects on tissue homeostasis via induction of both further MMPs synthesis
and aberrant TGFbsignaling. In the elastin-rich reticular dermis, microfibril remodeling may, in turn, not only up-regulate
MMP expression and tropoelastin synthesis but also prevent the formation of structurally competent elastic fibers (elasto-
gensis). TGFb, transforming growth factor b. To see this illustration in color, the reader is referred to the web version of this
article at www.liebertpub.com/ars
otherwise biochemically dissimilar elastic fiber components
(fibrillin-1/2, fibulin-1/5, LTBP-1/2, MAGP-1 LOX, and
LOXL-1/2/3) are Cys-, Trp-, and Tyr-rich, located primarily in
the papillary dermis as arborizing microfibrils or on the pe-
riphery of elastic fibers, and, in the case of fibrillin-1, are sus-
ceptible to glycation (5, 71). We suggest, therefore, that UVR
will interact with multiple UVR-chromophore-rich proteins in
both the extracellular and intracellular environments to induce
direct, oxidative, and enzymatic matrix remodeling.
Although the skin undergoes profound architectural and
functional remodeling with chronic UVR exposure, the
causative mechanisms remain poorly defined. Given the in-
creasing evidence for the role of both intra- and extra-cellular
photosensitizers in mediating the production of ROS and
hence of oxidative damage and aberrant cell signaling, we
propose a new selective hit model of photoaging in which
proteins that are either readily glycated or which are rich in
Cys, Trp, and Tyr act as cutaneous chromophores. Human
skin, and in particular UVR-exposed skin, is an ideal model
system in which to study aging of less accessible connective
tissues, including blood vessels and lungs. The age-related
pathological remodeling that is associated with the accumu-
lation of damage by long-lived cellular components (DNA)
and ECM proteins in these tissues is associated with the action
of both glucose and ROS. Hence, identifying the key targets of
age-related modifications (such as elastic fiber components) is
an important step in understanding and hence ameliorating
and repairing the effects of aging.
This work was supported, in part, by a program grant
awarded to the authors by Alliance Boots, Nottingham, Uni-
ted Kingdom. In addition M.J.S., R.E.B.W. and C.E.M.G. are in
receipt of Medical Research Council UK funding and
C.E.M.G. is an NIHR Senior Investigator. We have also car-
ried out independent commercial studies funded by Bio-
Minerals NV; Croda Chemicals Europe Limited; Degussa AG;
Kao Corporation; L’Ore
´al Recherche; Oriflame GTC Limited;
Proctor & Gamble Technical Centers; and Unilever R&D
Colworth. However, no commercial organization exerted
editorial control over the contents of this article.
1. Agache PG, Monneur C, Leveque JL, and Derigal J.
Mechanical-properties and Young’s modulus of human-
skin in vivo. Arch Dermatol Res 269: 221–232, 1980.
2. Armstrong BK and Kricker A. The epidemiology of UV
induced skin cancer. J Photochem Photobiol B 63: 8–18, 2001.
3. Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD,
Shuttleworth CA, and Kielty CM. Fibrillin degradation by
matrix metalloproteinases: implications for connective tis-
sue remodelling. Biochem J 340: 171–181, 1999.
4. Askew EW. Work at high altitude and oxidative stress:
antioxidant nutrients. Toxicology 180: 107–119, 2002.
5. Atanasova M, Konova E, Betova T, and Baydanoff S. Non-
enzymatic glycation of human fibrillin-1. Gerontology 55:
73–81, 2009.
6. Bailey AJ. Molecular mechanisms of ageing in connective
tissues. Mech Ageing Dev 122: 735–755, 2001.
7. Balasubramanian D. Photodynamics of cataract: an update
on endogenous chromophores and antioxidants. Photochem
Photobiol 81: 498–501, 2005.
8. Baldock C, Sherratt MJ, Shuttleworth CA, and Kielty CM.
The supramolecular organization of collagen VI microfi-
brils. J Mol Biol 330: 297–307, 2003.
9. Behrens DT, Villone D, Koch M, Brunner G, Sorokin L,
Robenek H, Bruckner-Tuderman L, Bruckner P, and Han-
sen U. The epidermal basement membrane is a composite
of separate laminin- or collagen IV-containing networks
connected by aggregated perlecan, but not by nidogens. J
Biol Chem 287: 18700–18709, 2012.
10. Bensasson RV, Land EJ, Truscott TG. Excited States and Free
Radicals in Biology and Medicine Contributions from Flash
Photolysis and Pulse Radiolysis, New York: Oxford Uni-
versity Press, Inc., 1993, p. 448.
11. Bernerd F and Asselineau D. UVA exposure of human skin
reconstructed in vitro induces apoptosis of dermal fibro-
blasts: subsequent connective tissue repair and implications
in photoaging. Cell Death Differ 5: 792–802, 1998.
12. Bernstein EF, Chen YQ, Tamai K, Shepley KJ, Resnik KS,
Zhang H, Tuan R, Mauviel A, and Uitto J. Enhanced elastin
and fibrillin gene-expression in chronically photodamaged
skin. J Investig Dermatol 103: 182–186, 1994.
13. Bernstein EF, Underhill CB, Hahn PJ, Brown DB, and Uitto
J. Chronic sun exposure alters both the content and distri-
bution of dermal glycosaminoglycans. Br J Dermatol 135:
255–262, 1996.
14. Bhawan J, Andersen W, Lee J, Labadie R, and Solares G.
Photoaging versus intrinsic aging—a morphologic assess-
ment of facial skin. J Cutan Pathol 22: 154–159, 1995.
15. Birch-Machin MA. The role of mitochondria in ageing and
carcinogenesis. Clin Exp Dermatol 31: 548–552, 2006.
16. Booms P, Ney A, Barthel F, Moroy G, Counsell D, Gille C,
Guo G, Pregla R, Mundlos S, Alix AJP, and Robinson PN. A
fibrillin-1-fragment containing the elastin-binding-protein
GxxPG consensus sequence upregulates matrix metallo-
proteinase-1: biochemical and computational analysis.
J Mol Cell Cardiol 40: 234–246, 2006.
17. Briggaman RA. Biochemical-composition of the epidermal-
dermal junction and other basement membrane. J Investig
Dermatol 78: 1–6, 1982.
18. Carrino DA, Onnerfjord P, Sandy JD, Cs-Szabo G. Scott PG,
Sorrell JM, Heinegard D, and Caplan AI. Age-related
changes in the proteoglycans of human skin—Specific
cleavage of decorin to yield a major catabolic fragment in
adult skin. J Biol Chem 278: 17566–17572, 2003.
19. Chakraborti S, Mandal M, Das S, Mandal A, and Chakra-
borti T. Regulation of matrix metalloproteinases: an over-
view. Mol Cell Biochem 253: 269–285, 2003.
20. Chao CYL, Zheng YP, and Cheing GL. Epidermal thickness
and biomechanical properties of plantar tissues in diabetic
foot. Ultrasound Med Biol 37: 1029–1038,
21. Chung JH, Seo JY, Lee MK, Eun HC, Lee JH, Kang S, Fisher
GJ, and Voorhees JJ. Ultraviolet modulation of human
macrophage metalloelastase in human skin in vivo. J In-
vestig Dermatol 119: 507–512, 2002.
22. Clydesdale GJ, Dandie GW, and Muller HK. Ultraviolet
light induced injury: immunological and inflammatory ef-
fects. Immunol Cell Biol 79: 547–568, 2001.
23. Cooper DR and Davidson RJ. Effect of ultraviolet irradia-
tion on soluble collagen. Biochem J 97: 139–147, 1965.
24. Cooper DR and Davidson RJ. The effect of ultraviolet radi-
ation on collagen-fold formation. Biochem J 98: 655–661, 1966.
25. Cornwell KG, Lei P, Andreadis ST, and Pins GD. Cross-
linking of discrete self-assembled collagen threads: effects
on mechanical strength and cell-matrix interactions. J
Biomed Mater Res A 80A: 362–371, 2007.
26. Craven NM, Watson REB, Jones CJP, Shuttleworth CA,
Kielty CM, and Griffiths CEM. Clinical features of photo-
damaged human skin are associated with a reduction in
collagen VII. Br J Dermatol 137: 344–350, 1997.
27. Creed D. The photophysics and photochemistry of the
near-UV absoring amino-acids. 1. Tryptophan and its
simple derivatives. Photochem Photobiol 39: 537–562, 1984.
28. Davidson RJ and Cooper DR. The effect of ultraviolet irra-
diation on acid-soluble collagen. Biochem J 105: 965–969, 1967.
29. Davies MJ. Reactive species formed on proteins exposed to
singlet oxygen. Photochem Photobiol Sci 3: 17–25, 2004.
30. de Gruijl FR and Rebel H. Early events in UV carcinogenesis—
DNA damage, target cells and mutant p53 foci. Photochem
Photobiol 84: 382–387, 2008.
31. Diffey B. Human exposure to ultraviolet radiation. Semin
Dermatol 9: 2–10, 1990.
32. Diffey BL, Jansen CT, Urbach F, and Wulf HC. The stan-
dard erythema dose: a new photobiological concept. Pho-
todermatol Photoimmunol Photomed 13: 64–66, 1997.
33. Doyle JJ, Gerber EE, and Dietz HC. Matrix-dependent
perturbation of TGF beta signaling and disease. FEBS Lett
586: 2003–2015, 2012.
34. Du H, Fuh RCA, Li, JZ, Corkan LA, and Lindsey JS. Pho-
tochemCAD: a computer-aided design and research tool in
photochemistry. Photochem Photobiol 68: 141–142, 1998.
35. El-Domyati M, Attia S, Saleh F, Brown D, Birk DE, Gasparro
F, Ahmad H, and Uitto J. Intrinsic aging vs. photoaging:
a comparative histopathological, immunohistochemical,
and ultrastructural study of skin. Exp Dermatol 11: 398–405,
36. Escoffier C, de Rigal J, Rochefort A, Vasselet R, Leveque JL,
and Agache PG. Age-related mechanical properties of hu-
man skin: an in vivo study. J Invest Dermatol 93: 353–357,
37. Feelisch M, Kolb-Bachofen V, Liu D, Lundberg JO, Revelo
LP, Suschek CV, and Weller RB. Is sunlight good for our
heart? Eur Heart J 31: 1041–1045, 2010.
38. Fenske NA and Lober CW. Structural and functional
changes of normal aging skin. J Am Acad Dermatol 15: 571–
585, 1986.
39. Fisher GJ, Datta SC, Talwar HS, Wang Z-Q, Varani J, Kang
S, and Voorhees JJ. Molecular basis of sun-induced pre-
mature skin ageing and retinoid antagonism. Nature 379:
335–339, 1996.
40. This reference has been deleted.
41. Fisher GJ and Voorhees JJ. Molecular mechanisms of pho-
toaging and its prevention by retinoic acid: ultraviolet ir-
radiation induces MAP kinase signal transduction cascades
that induce Ap-1-regulated matrix metalloproteinases that
degrade human skin in vivo. J Investig Dermatol Symp Proc 3:
61–68, 1998.
42. Foote CS. Definition of type-I and type-II photosensitized
oxidation. Photochem Photobiol 54: 659, 1991.
43. Fujimori E. Changes induced by ozone and ultraviolet light
in type I collagen. Bovine Achilles tendon collagen versus
rat tail tendon collagen. Eur J Biochem 152: 299–306, 1985.
44. Garcia AJ, Vega MD, and Boettiger D. Modulation of cell
proliferation and differentiation through substrate- depen-
dent changes in fibronectin conformation. Mol Biol Cell 10:
785–798, 1999.
45. Gems D and Doonan R. Antioxidant defense and aging in
C. elegans Is the oxidative damage theory of aging wrong?
Cell Cycle 8: 1681–1687, 2009.
46. Ghersetich I, Lotti T, Campanile G, Grappone C, and Dini
G. Hyaluronic-acid in cutaneous intrinsic aging. Int J Der-
matol 33: 119–122, 1994.
47. Gilchrest BA, Murphy GF, and Soter NA. Effect of chrono-
logic aging and ultraviolet-irradiation on Langerhans cells in
human epidermis. J Investig Dermatol 79: 85–88, 1982.
48. Glossmann H. Vitamin D, UV, and skin cancer in the elderly:
to expose or not to expose? Gerontology 57: 350–353, 2011.
49. Godar DE, Landry RJ, and Lucas AD. Increased UVA ex-
posures and decreased cutaneous Vitamin D-3 levels may
be responsible for the increasing incidence of melanoma.
Med Hypotheses 72: 434–443, 2009.
50. Graham HK, Holmes DF, Watson RB, and Kadler KE.
Identification of collagen fibril fusion during vertebrate
tendon morphogenesis. The process relies on unipolar fi-
brils and is regulated by collagen-proteoglycan interaction.
J Mol Biol 295: 891–902, 2000.
51. Grant WB. An estimate of premature cancer mortality in
the US due to inadequate doses of solar ultraviolet-B ra-
diation. Cancer 94: 1867–1875, 2002.
52. GretherBeck S, Buettner R, and Krutmann J. Ultraviolet A
radiation-induced expression of human genes: molecular
and photobiological mechanisms. Biol Chem 378: 1231–1236,
53. Guan E, Smilow S, Rafailovich M, and Sokolov J. De-
termining the mechanical properties of rat skin with digital
image speckle correlation. Dermatology 208: 112–119, 2004.
54. Hamill KJ, Paller AS, and Jones JCR. Adhesion and mi-
gration, the diverse functions of the laminin alpha 3 sub-
unit. Dermatol Clin 28: 79–87, 2010.
55. Harrison GI and Young AR. Ultraviolet-radiation induced
erythema in human skin. Methods 28: 14–19, 2002.
56. Harrison GI, Young AR, and McMahon SB. Ultraviolet
radiation-induced inflammation as a model for cutaneous
hyperalgesia. J Investig Dermatol 122: 183–189, 2004.
57. Hayashi T, Curranpatel S, and Prockop DJ. Thermal-
stability of the triple helix of type-I procollagen and colla-
gen. Precautions for minimizing ultraviolet damage to
proteins during circular-dichromism studies. Biochemistry
18: 4182–4187, 1979.
58. Holick MF. Vitamin D deficiency. N Engl J Med 357:
266–281, 2007.
59. Hussein MR. Ultraviolet radiation and skin cancer: molec-
ular mechanisms. J Cutan Pathol 32: 191–205, 2005.
60. Ishii N, Nakane H, and Ishida-Yamamoto A. Application
and limitations of three-dimensional reconstruction of the
epidermal/dermal junction using electron microscopy. J
Dermatol Sci 32: 231–235, 2003.
61. Jariashvili K, Madhan B, Brodsky B, Kuchava A,
Namicheishvili L, and Metreveli N. UV damage of colla-
gen: insights from model collagen peptides. Biopolymers 97:
189–198, 2012.
62. Jeanmaire C, Danoux L, and Pauly G. Glycation during
human dermal intrinsic and actinic ageing: an in vivo and
in vitro model study. Br J Dermatol 145: 10–18, 2001.
63. Jennissen HP. Ubiquitin and the enigma of intracellular
protein-degradation. Eur J Biochem 231: 1–30, 1995.
64. Kadler KE, Holmes DF, Trotter JA, and Chapman JA.
Collagen fibril formation. Biochem J 316: 1–11, 1996.
65. Kadoya K, Sasaki T, Kostka G, Timpl R, Matsuzaki K,
Kumagai N, Sakai LY, Nishiyama T, and Amano S. Fibulin-
5 deposition in human skin: decrease with ageing and ul-
traviolet B exposure and increase in solar elastosis. Br J
Dermatol 153: 607–612, 2005.
66. Kaji Y, Amano S, Usui T, Suzuki K, Tanaka S, Oshika T,
Nagai R, and Horiuchi S. Advanced glycation end products
in Descemet’s membrane and their effect on corneal en-
dothelial cell. Curr Eye Res 23: 469–477, 2001.
67. Kato Y, Uchida K, and Kawakishi S. Oxidative-degradation
of collagen and its model peptide by ultraviolet-irradiation.
J Agric Food Chem 40: 373–379, 1992.
68. Katzberg AA. The area of the dermo-epidermal junction in
human skin. Anat Rec 131: 717–723, 1958.
69. Keeley FW, Bellingham CM, and Woodhouse KA. Elastin
as a self-organizing biomaterial: use of recombinantly ex-
pressed human elastin polypeptides as a model for inves-
tigations of structure and self-assembly of elastin. Philos
Trans R Soc Lond B Biol Sci 357: 185–189, 2002.
70. Kielty CM, Davies SJ, Phillips JE, Jones CJP, Shuttleworth
CA, and Charles SJ. Marfan Syndrome—fibrillin expression
and microfibrillar abnormalities in a family with predom-
inant ocular defects. J Med Genet 32: 1–6, 1995.
71. Kielty CM, Sherratt MJ, and Shuttleworth CA. Elastic fi-
bres. J Cell Sci 115: 2817–2828, 2002.
72. Krammer A, Craig D, Thomas WE, Schulten K, and Vogel V.
A structural model for force regulated integrin binding to
fibronectin’s RGD-synergy site. Matrix Biol 21: 139–147, 2002.
73. Kretsos K and Kasting GB. Dermal capillary clearance:
physiology and modeling. Skin Pharmacol Physiol 18: 55–74,
74. Kumakiri M, Hashimoto K, and Willis I. Biologic changes
due to long-wave ultraviolet irradiation on human skin:
ultrastructural study. J Investig Dermatol 69: 392–400, 1977.
75. Labat-Robert J. Cell-Matrix interactions, the role of fibro-
nectin and integrins. A survey. Pathol Biol 60: 15–19, 2012.
76. Lagarde JM, George J, Soulcie R, and Black D. Automatic
measurement of dermal thickness from B-scan ultrasound
images using active contours. Skin Res Technol 11: 79–90,
77. Langton AK, Sherratt MJ, Griffiths CEM, and Watson REB.
A new wrinkle on old skin: the role of elastic fibres in skin
ageing. Int J Cosmet Sci 32: 330–339, 2010.
78. Lavker RM. Structural alterations in exposed and unex-
posed aged skin. J Investig Dermatol 73: 59–66, 1979.
79. Law MR and Morris JK. Why is mortality higher in poorer
areas and in more northern areas of England and Wales? J
Epidemiol Commun Health 52: 344–352, 1998.
80. Layton BE and Sastry AM. Equal and local-load-sharing
micromechanical models for collagens: quantitative com-
parisons in response of non-diabetic and diabetic rat tissue.
Acta Biomater 2: 595–607, 2006.
81. Lin, JY and Fisher DE. Melanocyte biology and skin pig-
mentation. Nature 445: 843–850, 2007.
82. Lorenz K, Sicker M, Schmelzer E, Rupf T, Salvetter J,
Schulz-Siegmund M, and Bader A. Multilineage differen-
tiation potential of human dermal skin-derived fibroblasts.
Exp Dermatol 17: 925–932, 2008.
83. Lowell S, Jones P, Le Roux I, Dunne J, and Watt FM. Sti-
mulation of human epidermal differentiation by Delta-
Notch signalling at the boundaries of stem-cell clusters.
Curr Biol 10: 491–500, 2000.
84. Lumpkin EA and Caterina MJ. Mechanisms of sensory
transduction in the skin. Nature 445: 858–865, 2007.
85. MacKenzie LA. The analysis of the ultraviolet-radiation
doses required to produce erythemal responses in normal
skin. Br J Dermatol 108: 1–9, 1983.
86. Madison KC. Barrier function of the skin: ‘‘La Raison d’Etre’
of the epidermis. JInvestigDermatol121: 231–241, 2003.
87. Manuskiatti W and Maibach HI. Hyaluronic acid and skin:
wound healing and aging. Int J Dermatol 35: 539–544, 1996.
88. Matsumura Y and Ananthaswamy HN. Toxic effects of
ultraviolet radiation on the skin. Toxicol Appl Pharmacol 195:
298–308, 2004.
89. McKenzie RL, Liley JB, and Bjorn LO. UV Radiation: bal-
ancing risks and benefits. Photochem Photobiol 85: 88–98, 2009.
90. Menter JM, Cornelison LM, Cannick L, Patta AM, Dowdy
JC, Sayre RM, Abukhalaf IK, Silvestrov NS, and Willis I.
Effect of UV on the susceptibility of acid-soluble Skh-1
hairless mouse collagen to collagenase. Photodermatol Pho-
toimmunol Photomed 19: 28–34, 2003.
91. Menter JM, Patta AM, Sayre RM, Dowdy J, and Willis I.
Effect of UV irradiation on type I collagen fibril formation
in neutral collagen solutions. Photodermatol Photoimmunol
Photomed 17: 114–120, 2001.
92. Merad M, Ginhoux F, and Collin M. Origin, homeostasis
and function of Langerhans cells and other langerin-
expressing dendritic cells. Nat Rev Immunol 8: 935–947,
93. Metreveli N, Namicheishvili L, Jariashvili K, Mrevlishvili
G, and Sionkowska A. Mechanisms of the influence of UV
irradiation on collagen and collagen-ascorbic acid solu-
tions. Int J Photoenergy 2006: 4, 2006.
94. Metreveli NO, Jariashvili KK, NamicheishviliB LO, Svin-
tradze DV, Chikvaidze EN, Sionkowska A, and Skopinska
J. UV-vis and FT-IR spectra of ultraviolet irradiated colla-
gen in the presence of antioxidant ascorbic acid. Ecotoxicol
Environ Saf 73: 448–455, 2010.
95. Metreveli NO, Namicheishvili LO, Dzhariashvili KK,
Chikvaidze EN, and Mrevlishvili GM. Microcalorimetric
and electron spin resonance study of the influence of UV
radiation on collagen. Biophysics 51: 29–32, 2006.
96. Miles CA, Sionkowska A, Hulin SL, Sims YJ, Avery NC,
and Bailey AJ. Identification of an intermediate state in the
helix-coil degradation of collagen by ultraviolet light. J Biool
Chem 275: 33014–33020, 2000.
97. Mitchell RE. Chronic solar dermatosis—a light and electron
microscopic study of dermis. J Investig Dermatol 48: 203–
220, 1967.
98. Miyata T, Sohde T, Rubin AL, and Stenzel KH. Effects of
ultraviolet irradiation on native and telopeptide-poor col-
lagen. Biochim Biophys Acta 229: 672–680, 1971.
99. Montagna W, Kirchner S, and Carlisle K. Histology of sun-
damaged human-skin. J Am Acad Dermatol 21: 907–918,
100. Moreau KL and King JA. Protein misfolding and aggrega-
tion in cataract disease and prospects for prevention. Trends
Mol Med 18: 273–282, 2012.
101. Moretti FA, Chauhan AK, Iaconcig A, Porro F, Baralle FE,
and Muro AF. A major fraction of fibronectin present in the
extracellular matrix of tissues is plasma-derived. J Biol
Chem 282: 28057–28062, 2007.
102. Morita A. Tobacco smoke causes premature skin aging. J
Dermatol Sci 48: 169–175, 2007.
103. Myint E, Brown DJ, Ljubimov AV, Kyaw M, and Kenney
MC. Cleavage of human corneal type VI collagen alpha 3
chain by matrix metalloproteinase-2. Cornea 15: 490–496,
104. Narayanan DL, Saladi RN, and Fox JL. Ultraviolet radia-
tion and skin cancer. Int J Dermatol 49: 978–986,
105. Naylor EC, Watson REB, and Sherratt MJ. Molecular as-
pects of skin ageing. Maturitas 69: 249–256, 2011.
106. Neptune ER, Frischmeyer PA, Arking DE, Myers L,
Bunton TE, Gayraud B, Ramirez F, Sakai LY, and Dietz
HC. Dysregulation of TGF-beta activation contributes to
pathogenesis in Marfan syndrome. Nat Genet 33: 407–411,
107. Neumann C, Yu A, Welge-Lussen U, Lutjen-Drecoll E, and
Birke M. The effect of TGF-beta 2 on elastin, type VI col-
lagen, and components of the proteolytic degradation sys-
tem in human optic nerve astrocytes. Investig Ophthalmol
Vis Sci 49: 1464–1472, 2008.
108. Ogden S and Griffiths TW. A review of minimally invasive
cosmetic procedures. Br J Dermatol 159: 1036–1050, 2008.
109. Oh JH, Kim YK, Jung JY, Shin JE, Kim KH, Cho KH, Eun
HC, and Chung JH. Intrinsic aging- and photoaging-
dependent level changes of glycosaminoglycans and their
correlation with water content in human skin. J Dermatol Sci
62: 192–201,
110. Pasternak B and Aspenberg P. Metalloproteinases and their
inhibitors-diagnostic and therapeutic opportunities in or-
thopedics. Acta Orthop 80: 693–703, 2009.
111. Pattison DI, Rahmanto AS, and Davies MJ. Photo-oxidation
of proteins. Photochem Photobiol Sci 11: 38–53,
112. This reference has been deleted.
113. Paunel AN, Dejam A, Thelen S, Kirsch M, Horstjann M,
Gharini P, Murtz M, Kelm M, de Groot H, Kolb-Bachofen
V, and Suschek CV. Enzyme-independent nitric oxide for-
mation during UVA challenge of human skin: character-
ization, molecular sources, and mechanisms. Free Radic Biol
Med 38: 606–615, 2005.
114. Proksch E, Brandner JM, and Jensen J-M. The skin: an in-
dispensable barrier. Exp Dermatol 17: 1063–1072, 2008.
115. Prost-Squarcioni C. Histology of skin and hair follicle. Med
Sci 22: 131–137, 2006.
116. Rabotyagova OS, Cebe P, and Kaplan DL. Collagen struc-
tural hierarchy and susceptibility to degradation by ultra-
violet radiation. Mater Sci Eng C Mater Biol Appl 28: 1420–
1429, 2008.
117. Rajgopalan S, Meng XP, Ramasamy S, Harrison DG, and
Galis ZS. Re-active oxygen species produced by macrophage-
derived foam cells regulate the activity of the vascular
metalloproteinases in vitro: implication for atherosclerotic
plaque stability. J Clin Investig 98: 2572–2579, 1996.
118. Ramirez F. Fibrillin mutations in Marfan syndrome and
related phenotypes. Curr Opin Genet Dev 6: 309–315, 1996.
119. Rittie L and Fisher GJ. UV-light-induced signal cascades
and skin aging. Ageing Res Rev 1: 705–720, 2002.
120. Ritz-Timme S and Collins MJ. Racemization of aspartic acid
in human proteins. Ageing Res Rev 1: 43–59, 2002.
121. Robert C, Lesty C, and Robert AM. Aging of the skin—
study of elastic fiber network modifications by computer-
ized image-analysis. Gerontology 34: 291–296, 1988.
122. Rosenbloom J, Castro SV, and Jimenez SA. Narrative re-
view: fibrotic diseases: cellular and molecular mecha-
nisms and novel therapies. Ann Intern Med 152: 159–166,
123. Saarialho-Kere U, Kerkela E, Jeskanen L, Hasan T, Pierce R,
Starcher B, Raudasoja R, Ranki A, Oikarinen A, and Vaa-
lamo M. Accumulation of matrilysin (MMP-7) and mac-
rophage metalloelastase (MMP-12) in actinic damage. J
Investig Dermatol 113: 664–672, 1999.
124. Sandby-Moller J, Poulsen T, and Wulf HC. Epidermal
thickness at different body sites: relationship to age, gen-
der, pigmentation, blood content, skin type and smoking
habits. Acta Derm Venereol 83: 410–413, 2003.
125. Sander CS, Chang H, Salzmann S, Muller CSL, Ekanayake-
Mudiyanselage S, Elsner P, and Thiele JJ. Photoaging is
associated with protein oxidation in human skin in vivo. J
Investig Dermatol 118: 618–625, 2002.
126. Sato K, Kang WH, Saga K, and Sato KT. Biology of sweat
glands and their disorders. 1. Normal sweat gland-
function. J Am Acad Dermatol 20: 537–563, 1989.
127. Scherer D and Kumar R. Genetics of pigmentation in skin
cancer—a review. Mutat Res 705: 141–153, 2010.
128. Schwartz E and Kligman LH. Topical tretinoin increases
the tropoelastin and fibronectin content of hairless mouse
skin. J Investig Dermatol 104: 518–522, 1995.
129. Sherratt MJ. Tissue elasticity and the ageing elastic fibre.
Age 31: 305–325, 2009.
130. Sherratt MJ, Bax DV, Chaudhry SS, Hodson N, Lu JR,
Saravanapavan P, and Kielty CM. Substrate chemistry in-
fluences the morphology and biological function of ad-
sorbed extracellular matrix assemblies. Biomaterials 26:
7192–7206, 2005.
131. Sherratt MJ, Bayley CP, Reilly SM, Gibbs NK, Griffiths
CEM, and Watson REB. Low-dose ultraviolet radiation
selectively degrades chromophore-rich extracellular matrix
components. J Pathol 222: 32–40, 2010.
132. Sherratt MJ, Holmes DF, Shuttleworth CA, and Kielty CM.
Substrate-dependent morphology of supramolecular as-
semblies: fibrillin and type-VI collagen microfibrils. Biophys
J86: 3211–3222, 2004.
133. Shimomura Y and Christiano AM. Biology and genetics of
hair. Annu Rev Genom Hum Genet 11: 109–132, 2010.
134. Singh P, Carraher C, and Schwarzbauer JE. Assembly of
fibronectin extracellular matrix. Annu Rev Cell Dev Biol 26:
397–419, 2010.
135. Sionkowska A and Kaminska A. Changes induced by ul-
traviolet light in fluorescence of collagen in the presence of
beta-carotene. J Photochem Photobiol Chem 120: 207–210,
136. Sionkowska A and Kaminska A. Thermal helix-coil tran-
sition in UV irradiated collagen from rat tail tendon. Int J
Biol Macromol 24: 337–340, 1999.
137. Sionkowska A, Skopinska J, Wisniewski M, and Leznicki
A. Spectroscopic studies into the influence of UV radiation
on elastin in the presence of collagen. J Photochem Photobiol
B Biol 86: 186–191, 2007.
138. Sionkowska A, Skopinska J, Wisniewski M, Leznicki A,
and Fisz J. Spectroscopic studies into the influence of UV
radiation on elastin hydrolysates in water solution. J Pho-
tochem Photobiol B Biol 85: 79–84, 2006.
139. Slatter DA, Avery NC, and Bailey AJ. Collagen in its fi-
brillar state is protected from glycation. Int J Biochem Cell
Biol 40: 2253–2263, 2008.
140. Starborg T, Lu Y, Kadler KE, and Holmes DF. Electron
microscopy of collagen fibril structure in vitro and in vivo
including three-dimensional reconstruction. Methods Cell
Biol 88: 319–345, 2008.
141. Stefani M and Dobson CM. Protein aggregation and ag-
gregate toxicity: new insights into protein folding, mis-
folding diseases and biological evolution. J Mol Med (Berl)
81: 678–699, 2003.
142. Stoevesandt J, Borozdin W, Girschick G, Hamm H, Hocht
B, Kohlhase J, Volz A, Wiewrodt B, and Wirbelauer J.
Lethal junctional epidermolysis bullosa with pyloric
atresia due to compound heterozygosity for two novel
mutations in the integrin b4 gene. Klin Padiatr 224: 8–11,
143. Strojek K, Ziora D, Sroczynski JW, and Oklek K. Pulmon-
ary complications of type-1 (insulin-dependent) diabetic
patients. Diabetologia 35: 1173–1176, 1992.
144. Sumikawa E, Matsumoto Y, Sakemura R, Fujii M, and
Ayusawa D. Prolonged unbalanced growth induces cellu-
lar senescence markers linked with mechano transduction
in normal and tumor cells. Biochem Biophys Res Commun
335: 558–565, 2005.
145. Takema Y and Imokawa G. The effects of UVA and UVB
irradiation on the viscoelastic properties of hairless mouse
skin in vivo. Dermatology 196: 397–400, 1998.
146. Takema Y, Yorimoto Y, Kawai M, and Imokawa G. Age-
related-changes in the elastic properties and thickness of
human facial skin. Br J Dermatol 131: 641–648, 1994.
147. Talwar HS, Griffiths CEM, Fisher GJ, Hamilton TA, and
Voorhees JJ. Reduced type-I and type-III procollagens in
photodamaged adult human skin. J Investig Dermatol 105:
285–290, 1995.
148. Tarsio JF, Wigness B, Rhode TD, Rupp WM, Buchwald H,
and Furcht LT. Nonenzymatic glycation of fibronectin and
alterations in the molecular association of cell matrix and
basement membrane components in diabete-mellitus. Dia-
betes 34: 477–484, 1985.
149. Thurstan SA, Gibbs NK, Langton AK, Griffiths CEM,
Watson REB, and Sherratt MJ. Chemical consequences of
cutaneous photoageing. Chem Central J 6: 34, 2012.
150. Thurstan SA, Watson REB, Griffiths CEM, Gibbs NK, and
Sherratt MJ. A common pathway for age-related protein
oxidation and photoageing. J Investig Dermatol 131: S104–
S104, 2011.
151. Tian H, Mythreye K, Golzio C, Katsanis N, and Blobe GC.
Endoglin mediates fibronectin/alpha 5 beta 1 integrin and
TGF-beta pathway crosstalk in endothelial cells. EMBO J
31: 3885–3900, 2012.
152. Timar F, Soos G, Szende B, and Horvath A. Interdigitation
index—a parameter for differentiating between young
and older skin specimens. Skin Res Technol 6: 17–20,
153. Trautinger F. Mechanisms of photodamage of the skin and
its functional consequences for skin ageing. Clin Exp Der-
matol 26: 573–577, 2001.
154. Veidal SS, Karsdal MA, Vassiliadis E, Nawrocki A, Larsen
MR, Quoc HTN, Hagglund P, Luo YY, Zheng QL, Vainer B,
and Leeming DJ. MMP mediated degradation of type
VI collagen is highly associated with liver fibrosis—
identification and validation of a novel biochemical marker
assay. PLoS One 6: 9, 2011.
155. Verzijl N, DeGroot J, Oldehinkel E, Bank RA, Thorpe SR,
Baynes JW, Bayliss MT, Bijlsma JWJ, Lafeber F, and Te-
Koppele JM. Age-related accumulation of Maillard reaction
products in human articular cartilage collagen. Biochem J
350: 381–387, 2000.
156. Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons
TJ, Bijlsma JWJ, Lafeber F, Baynes JW, and TeKoppele JM.
Effect of collagen turnover on the accumulation of ad-
vanced glycation end products. J Biol Chem 275: 39027–
39031, 2000.
157. Volker W, Ringelstein EB, Dittrich R, Maintz D, Nassen-
stein I, Heindel W, Grewe S, and Kuhlenbaumer G. Mor-
phometric analysis of collagen fibrils in skin of patients
with spontaneous cervical artery dissection. J Neurol Neu-
rosurg Psychiatry 79: 1007–1012, 2008.
158. Voss P, Hajimiragha H, Engels M, Ruhwiedel C, Calles C,
Schroeder P, and Grune T. Irradiation of GAPDH: a model
for environmentally induced protein damage. Biol Chem
388: 583–592, 2007.
159. Wan P, Edwards C, Zheng J, and Ainstey A. Validation of a
novel high-intensity LED light source for skin phototesting
at 365 nm. Photodermatol Photoimmunol Photomed 28: 80–83,
160. Warren R, Gartstein V, Kligman AM, Montagna W, Al-
lendorf RA, and Ridder GM. Age, sunlight, and facial skin:
a histologic and quantitative study. J Am Acad Dermatol 25:
751–760, 1991.
161. Watson REB, Ball SG, Craven NM, Boorsma J, East CL,
Shuttleworth CA, Kielty CM, and Griffiths CEM. Dis-
tribution and expression of type VI collagen in photoaged
skin. Br J Dermatol 144: 751–759, 2001.
162. Watson REB, Craven NM, Kang SW, Jones CJP, Kielty CM,
and Griffiths CEM. A short-term screening protocol, using
fibrillin-1 as a reporter molecule, for photoaging repair
agents. J Investig Dermatol 116: 672–678, 2001.
163. Watson REB, Griffiths CEM, Craven NM, Shuttleworth CA,
and Kielty CM. Fibrillin-rich microfibrils are reduced in
photoaged skin. Distribution at the dermal-epidermal
junction. J Investig Dermatol 112: 782–787, 1999.
164. Winlove CP, Parker KH, Avery NC, and Bailey AJ. Inter-
actions of elastin and aorta with sugars in vitro and their
effects on biochemical and physical properties. Diabetologia
39: 1131–1139, 1996.
165. Wondrak GT, Jacobson EL, and Jacobson MK. Photo-
sensitization of DNA damage by glycated proteins. Photo-
chem PhotobiolSci 1: 355–363, 2002.
166. Wondrak GT, Jacobson MK, and Jacobson EL. Endogenous
UVA-photosensitizers: mediators of skin photodamage and
novel targets for skin photoprotection. Photochem Photobiol
Sci 5: 215–237, 2006.
167. Wondrak GT, Roberts MJ, Cervantes-Laurean D, Jacobson
MK, and Jacobson EL. Proteins of the extracellular matrix
are sensitizers of photo-oxidative stress in human skin cells.
J Investig Dermatol 121: 578–586, 2003.
168. Wondrak GT, Roberts MJ, Jacobson MK, and Jacobson EL.
3-hydroxypyridine chromophores are endogenous sensi-
tizers of photooxidative stress in human skin cells. J Biol
Chem279: 30009–30020, 2004.
169. Wondrak GT, Roberts MJ, Jacobson MK, and Jacobson EL.
Photosensitized growth inhibition of cultured human skin
cells: mechanism and suppression of oxidative stress from
solar irradiation of glycated proteins. J Investig Dermatol
119: 489–498, 2002.
170. Yaar M and Gilchrest BA. Photoageing: mechanism,
prevention and therapy. Br J Dermatol 157: 874–887,
171. Yang SH, Nugent MA, and Panchenko MP. EGF antago-
nizes TGF-beta-induced tropoelastin expression in lung fi-
broblasts via stabilization of Smad corepressor TGIF. Am J
Physiol Lung Cell Mol Physiol 295: L143–L151, 2008.
172. Young AR. Chromophores in human skin. Phys Med Biol
42: 789–802, 1997.
173. Young AR and Walker SL. UV radiation, vitamin D and
human health: an unfolding controversy—introduction.
Photochem Photobiol 81: 1243–1245, 2005.
174. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW,
Kimmelman J, Remington L, Jacks T, and Brash DE. Sunburn
and p53 in the onset of skin-cancer. Nature 372: 773–776,
175. Zittermann A. Vitamin D and disease prevention with
special reference to cardiovascular disease. Prog Biophys
Mol Biol 92: 39–48, 2006.
Address correspondence to:
Dr. Michael John Sherratt
Centre for Tissue Injury and Repair
Institute of Inflammation and Repair
The University of Manchester
Manchester Academic Health Science Centre
Manchester M13 9PT
United Kingdom
E-mail: michael.sherratt@manchester.ac.uk
Date of first submission to ARS Central, September 28, 2013;
date of acceptance, October 13, 2013.
Abbreviations Used
AFM ¼atomic force microscope/microscopy
DEJ ¼dermal–epidermal junction
DNA ¼deoxyribonucleic acid
ECM ¼extracellular matrix
LTBP ¼latent transforming growth factor b-binding
LOX ¼lysyl oxidase
LOXL ¼lysyl oxidase like
MAGP ¼microfibril-associated glycoprotein
MED ¼minimal erythemal dose
MMP ¼matrix metalloproteinase
NAD(P)H ¼nicotinamide adenine dinucleotide
ROS ¼reactive oxygen species
SSR ¼solar-simulated radiation
TGFb¼transforming growth factor b
UVR ¼ultraviolet radiation
UVA/B/C ¼ultraviolet A/B/C
... UVR also stimulates the degradation of dermal ECM components, e.g., collagen, elastin, and glycoproteins [63]. UVR induces collagen fragmentation and aggregation, i.e., similar changes as encountered in the intrinsic aging process but much faster than in normal aging [63,64]. ...
... UVR also stimulates the degradation of dermal ECM components, e.g., collagen, elastin, and glycoproteins [63]. UVR induces collagen fragmentation and aggregation, i.e., similar changes as encountered in the intrinsic aging process but much faster than in normal aging [63,64]. UVR exposure significantly increased the expression and secretion of matrix metalloproteinases which induced the degradation of ECM proteins [65]. ...
Full-text available
Background Excessive exposure of the skin to UV radiation (UVR) triggers a remodeling of the immune system and leads to the photoaging state which is reminiscent of chronological aging. Over 30 years ago, it was observed that UVR induced an immunosuppressive state which inhibited skin contact hypersensitivity. Methods Original and review articles encompassing inflammation and immunosuppression in the photoaging and chronological aging processes were examined from major databases including PubMed, Scopus, and Google Scholar. Results Currently it is known that UVR treatment can trigger a cellular senescence and inflammatory state in the skin. Chronic low-grade inflammation stimulates a counteracting immunosuppression involving an expansion of immunosuppressive cells, e.g., regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and regulatory dendritic cells (DCreg). This increased immunosuppressive activity not only suppresses the function of effector immune cells, a state called immunosenescence, but it also induces bystander degeneration of neighboring cells. Interestingly, the chronological aging process also involves an accumulation of pro-inflammatory senescent cells and signs of chronic low-grade inflammation, called inflammaging. There is also clear evidence that inflammaging is associated with an increase in anti-inflammatory and immunosuppressive activities which promote immunosenescence. Conclusion It seems that photoaging and normal aging evoke similar processes driven by the remodeling of the immune system. However, it is likely that there are different molecular mechanisms inducing inflammation and immunosuppression in the accelerated photoaging and the chronological aging processes.
... ROS is a major cause of endogenous aging, and its accumulation can directly damage DNA, proteins, and lipids, triggering the downregulation of collagen production and leading to dermal aging. The AP-1 transcription factor complex upregulates MMPs and promotes collagen catabolism [43,44]. Thus, COL-I content and MMP-1 enzyme activity and expression levels are important physicochemical indicators of skin aging. ...
Full-text available
This study investigated the effects of Lactobacillus curvatus fermentation on the oxidative stress attenuating effects of Euryale ferox on H2O2-induced human skin fibroblasts (HSF). The results showed that Lactobacillus curvatus fermentation (i) increases the content of the various bioactive components of Euryale ferox and is found to have smaller molecular weights of polysaccharides and polypeptides; (ii) increases the overall intracellular and extracellular antioxidant capacity of H2O2-induced HSF while reducing reactive oxygen species (ROS) levels. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) all showed simultaneous increases in activity. Aside from that, the Nrf2 and MAPK signaling pathways are activated to regulate downstream-associated proteins such as the Bax/Bcl-2 protein ratio, matrix metalloproteinase 1 (MMP-1) activity, and human type I collagen (COL-1). These results suggested that the fermentation of Euryale ferox with Lactobacillus curvatus enhances its antioxidant capacity and attenuates apoptosis and senescence caused by oxidative stress.
... In addition to natural aging caused by the body's natural cell metabolism, photoaging is the second largest cause of skin aging. UV radiation can affect the formation of type I collagen, resulting in a relative increase in type III collagen (3,4), which eventually leads to a decrease in mature collagen bundles and skin laxity and wrinkles. Components of the skin's dermal matrix, such as aminoglycans and proteoglycans, are also implicated in photoaging (5). ...
... Indeed, UVC light is barely able to penetrate the skin's outermost layer, while UVB penetrates completely through the epidermis and marginally into the papillary dermis. Conversely, UVA affects the full thickness of the dermis, both the papillary and reticular layers, including the underlying subcutaneous tissue [18,36]. ...
Full-text available
Melanoma is the most aggressive and life-threatening form of skin cancer. Key molecular events underlying the melanocytic transformation into malignant melanoma mainly involve gene mutations in which exposure to ultraviolet (UV) radiation plays a prominent role. However, several aspects of UV-induced melanomagenesis remain to be explored. Interestingly, redox-mediated signaling and perturbed microRNA (miRNA) profiles appear to be interconnected contributing factors able to act synergistically in melanoma initiation and progression. Since UV radiation can promote both redox imbalance and miRNA dysregulation, a harmful crosstalk between these two key cellular networks, with UV as central hub among them, is likely to occur in skin tissue. Therefore, decoding the complex circuits that orchestrate the interaction of UV exposure, oxidative stress, and dysregulated miRNA profiling can provide a deep understanding of the molecular basis of the melanomagenesis process. Furthermore, these mechanistic insights into the reciprocal regulation between these systems could have relevant implications for future therapeutic approaches aimed at counteracting UV-induced redox and miRNome imbalances for the prevention and treatment of malignant melanoma. In this review, we illustrate current information on the intricate connection between UV-induced dysregulation of redox-sensitive miRNAs and well-known signaling pathways involved in the malignant transformation of normal melanocytes to malignant melanoma.
... After exposure to UV radiation, the amorphous elastic fibers in the skin tissue exhibit excessive accumulation, whereas the collagen fibers appear to be abnormally broken and structurally disordered, gradually forming wrinkles in the skin (Varani et al., 2004;Watson et al., 2014). Moreover, when skin cells are exposed to excessive UV radiation, reactive oxygen species (ROS) can accumulate in the cells, leading to damage to skin cells and the extracellular matrix surrounding the cells (Morita, 2007;Giangreco et al., 2008). ...
Full-text available
Although lactic acid bacteria (LAB) were shown to be effective for preventing photoaging, the underlying molecular mechanisms have not been fully elucidated. Accordingly, we examined the anti-photoaging potential of 206 LAB isolates and discovered 32 strains with protective activities against UV-induced injury. All of these 32 LABs exhibited high levels of 2,2-diphenyl-picrylhydrazyl, as well as hydroxyl free radical scavenging ability (46.89–85.13% and 44.29–95.97%, respectively). Genome mining and metabonomic verification of the most effective strain, Limosilactobacillus fermentum XJC60, revealed that the anti-photoaging metabolite of LAB was nicotinamide (NAM; 18.50 mg/L in the cell-free serum of XJC60). Further analysis revealed that LAB-derived NAM could reduce reactive oxygen species levels by 70%, stabilize the mitochondrial membrane potential, and increase the NAD+/NADH ratio in UV-injured skin cells. Furthermore, LAB-derived NAM downregulated the transcript levels of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-1β, IL-6, and IL-8 in skin cells. In vivo, XJC60 relieved imflammation and protected skin collagen fiber integrity in UV-injured Guinea pigs. Overall, our findings elucidate that LAB-derived NAM might protect skin from photoaging by stabilizing mitochondrial function, establishing a therotical foundation for the use of probiotics in the maintenance of skin health.
... UV irradiation is the main external factor that causes skin aging and wrinkle formation [8,9]. Previous research showed that irradiating cells with UV light destroyed their morphology and induced apoptosis, which influenced extracellular matrix (ECM) production and secretion, leading to cellular malfunction [10]. ...
Full-text available
Ultraviolet-A (UVA) exposure is a major cause of skin aging and can induce oxidative damage and accelerate skin wrinkling. Many natural polysaccharides exhibit a UV protective effect. In research on Pholiota nameko polysaccharides (PNPs), a natural macromolecular polysaccharide (4.4–333.487 kDa), studies have shown that PNPs can significantly decrease elastase activity to protect against UVA-induced aging in Hs68 human dermal fibroblasts. Cellular experiments in the present study indicated that PNPs can protect against UVA-induced oxidative damage in Hs68 cells by inhibiting the production of reactive oxygen species. Furthermore, PNPs significantly attenuated UVA-induced cell aging by decreasing the protein expression of matrix metalloproteinase 1, 3, and 9. Pretreatment of Hs68 cells with PNP-40, PNP-60, and PNP-80 before UVA irradiation increased protein expression of tissue inhibitor metalloproteinase 1 by 41%, 42%, and 56% relative to untreated cells. In conclusion, this study demonstrates that PNPs are a natural resource with potentially beneficial effects in protecting against UVA-induced skin aging.
... In contrast, exposure to UVR, reactive oxygen species (ROS) and proteases can fragment ECM proteins. High concentrations of oxidants, such as H 2 O 2 , can completely degrade ECM proteins such as fibronectin and high doses of UVR can induce profound changes in collagen structure [66,67]. However, we have also shown that physiologically relevant doses of UVR can induce profound structural changes in proteins rich in amino acid residues, such as Cys, disulphidebonded Cys, Trp, Tyr and Met which can absorb UV (UV chromophores) or are oxidation sensitive [68,69]. ...
Full-text available
Extracellular matrix (ECM) proteins confer biomechanical properties, maintain cell phenotype and mediate tissue repair (via release of sequestered cytokines and proteases). In contrast to intracellular proteomes, where proteins are monitored and replaced over short time periods, many ECM proteins function for years (decades in humans) without replacement. The longevity of abundant ECM proteins, such as collagen I and elastin, leaves them vulnerable to damage accumulation and their host organs prone to chronic, age-related diseases. However, ECM protein fragmentation can potentially produce peptide cytokines (matrikines) which may exacerbate and/or ameliorate age- and disease-related ECM remodelling. In this review, we discuss ECM composition, function and degradation and highlight examples of endogenous matrikines. We then critically and comprehensively analyse published studies of matrix-derived peptides used as topical skin treatments, before considering the potential for improvements in the discovery and delivery of novel matrix-derived peptides to skin and internal organs. From this, we concluded that while the translational impact of matrix-derived peptide therapeutics is evident, the mechanisms of action of these peptides are poorly defined. Further, well-designed, multimodal studies are required.
In order to realize the full-spectrum lighting, excellent blue-cyan phosphors which can be excited by violet LED chips are particularly important to compensate the spectral cyan gap. Herein, we report...
Background: Although retinol skin care products improve the appearance of photoaged skin, there is a need for an effective retinol concentration that provides skin benefits without irritation. Objective: To compare the efficacy of topical 0.1%, 0.3% and 1% retinol in remodelling the cutaneous architecture in an in vivo experimental patch test study, and to determine tolerance of the most effective formulations when used in a daily in-use escalation study. Methods: For the patch test study, retinol products were applied under occlusion, to the extensor forearm of photoaged volunteers (n = 5; age range 66 - 84 years), and 3 mm skin biopsies obtained after 12-days. Effects of different retinol concentrations, and a vehicle control, on key epidermal and dermal biomarkers of cellular proliferation and dermal remodelling were compared to untreated baseline. Separately, participants (n = 218) recorded their tolerance to 0.3% or 1% retinol over a six-week, approved regimen, which gradually increased the facial applications to once nightly. Results: Retinol treatment induced a stepwise increase in epidermal thickness and induced the expression of stratum corneum proteins, filaggrin and KPRP. Retinol 0.3% and 1% were comparably effective at inducing keratinocyte proliferation in the epidermis, whilst reducing e-cadherin expression. Fibrillin-rich microfibril deposition was increased following treatment with 0.3% and 1% retinol (P < 0.01); other dermal components remained unaltered (e.g. fibronectin, collagen fibrils, elastin), and no evidence of local inflammation was detected. The in-use study found that 0.3% was better tolerated than 1% retinol, with fewer and milder adverse events reported (χ2 (1) = 23.97; P < 0.001). Conclusions: This study suggests that 1% retinol and 0.3% retinol concentrations were similarly effective at remodelling photodamaged skin in an in vivo model of long-term use. Use of 0.3% retinol in the escalation study was associated with fewer adverse reactions when applied daily. Hence, 0.3% retinol may be better tolerated than 1% retinol, thereby allowing longer-term topical application.
Full-text available
Depression is a common mental disorder that affects more than 264 million people worldwide. Anxiety, diabetes, Alzheimer’s disease, myocardial infarction, and cancer, among other disorders, are known to increase the risk of depression. Exposure to ultraviolet B (UVB) can cause human serotonin levels to increase. The vitamin D pathway is one mechanism through which ultraviolet light absorbed through the skin can affect mood; however, UVB exposure is known to increase the risk of cancer. In this study, we explored the effects of prolonged exposure to UVB on depression. Data were retrieved from the Taiwan National Health Insurance Research Database for 2008 to 2013. Each patient with depression was matched 1:4 with a comparison patient by sex and age (±5 years); thus, the study included 23,579 patients with depression and 94,316 healthy controls for comparison. The patients had been exposed to UVB for at least 1 year to observe the cumulative effect of UVB exposure. Based on the World Health Organization UV index, we divided the observation period data into five UV levels: low, moderate, high, very high, and extreme. A multivariate Poisson regression model was used to assess the risk of depression according to UVB exposure level, adjusting for sex, age, income, urbanization level, month, and comorbidities. The results revealed that the incidence rate ratio (IRR) for patients with depression was 0.889 for moderate levels (95% CI 0.835–0.947), 1.134 for high levels (95% CI: 1.022–1.260), 1.711 for very high levels (95% CI: 1.505–1.945), and 2.785 for extreme levels (95% CI: 2.439–3.180) when compared to low levels. Moderate levels of UVB lowered the risk of depression, while high levels of UVB gradually increased the risk. We propose that UVB at normal concentrations can effectively improve depression. However, exposure to high concentrations of UVB damage DNA results in physical diseases such as skin cancer, which increase the risk of depression.
Full-text available
Both the transforming growth factor β (TGF-β) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, α5β1 integrin, specifically increase TGF-β1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-β superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and α5β1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-β1 activates α5β1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. α5β1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating α5β1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/α5β1 integrin and TGF-β pathway crosstalk alter the responses of endothelial cells to TGF-β1, switching TGF-β1 from a promoter to a suppressor of migration, inhibiting TGF-β1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-β superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.
Abnormal and exaggerated deposition of extracellular matrix is the hallmark of many fibrotic diseases, including systemic sclerosis and pulmonary, liver, and kidney fibrosis. The spectrum of affected organs, the usually progressive nature of the fibrotic process, the large number of affected persons, and the absence of effective treatment pose an enormous challenge when treating fibrotic diseases. Delineation of the central role of transforming growth factor-beta (TGF-beta) and identification of the specific cellular receptors, kinases, and other mediators involved in the fibrotic process have provided a sound basis for development of effective therapies. The inhibition of signaling pathways activated by TGF-beta represents a novel therapeutic approach for the fibrotic disorders. One of these TGF-beta pathways results in the activation of the nonreceptor tyrosine kinase cellular Abelson (c-Abl), and c-Abl inhibitors, including imatinib mesylate, diminishing the fibrogenic effects of TGF-beta. Thus, recently acquired basic knowledge about the pathogenesis of the fibrotic process has enabled the development of novel therapeutic agents capable of modifying the deleterious effects of the fibrotic diseases.
— The photophysics and photochemistry of tryptophan and its simple derivatives is comprehensively reviewed with special emphasis on excitation by near-UV radiation. Topics explicitly discussed include the origins of large Stokes shifts in the fluorescence spectra, photoionization, the puzzle of multiple tryptophan fluorescence decay time, photochemical reactions in the presence and absence of oxygen, and the possible mechanisms of these reactions. A separate section reviews the photosensitizing properties of N-formylkynurenine, an important photooxidation product of tryptophan.
The influence of UV radiation (253.7nm) on collagen fluorescence in the absence, and presence, of β-carotene was investigated. It was found that UV radiation of 253.7nm causes irreversible destruction of tyrosyl and phenylalanyl residues. The fluorescence of collagen (excitation at 275nm, emission at 305nm) decreased rapidly during irradiation and a new fluorescence large band at 400–500nm formed under UV radiation. Smaller changes in the fluorescence of collagen in the presence of β-carotene suggest that it makes collagen less sensitive to the action of UV radiation.
The effects of ultraviolet irradiation on collagen and its model peptides were studied. Degradation of collagen was predominant in the system using gel filtration chromatography. The fragmentation was presumably due to oxidation of proline, since collagen is a proline-rich protein and proline residues on collagen markedly decreased with irradiation. To clarify the fragmentation mechanism, poly(L-proline) and (Pro-Pro-Gly)10 as models of a collagen molecule were used and their oxidation was investigated. Glutamic acid, gamma-aminobutyric acid (GABA), and ammonia from the hydrolysates of the irradiated prolyl peptides were identified by amino acid analysis. It was presumed that GABA was generated from a 2-pyrrolidone structure by acid hydrolysis. To confirm this prediction, N-tert-butoxycarbonyl (Boc)-L-proline and N-tert-Boc-L-prolylglycine were exposed to ultraviolet light, and the irradiation products were isolated and characterized. Then, N-tert-Boc-2-pyrrolidone was identified from both UV-irradiated N-tert-Boc-L-proline and N-tert-Boc-L-prolylglycine. We proposed that the formation of the 2-pyrrolidone compound must contribute to the fragmentation of prolyl peptide on the basis of its structural property.
Skin cancer is the most common type of cancer in fair-skinned populations in many parts of the world. The incidence, morbidity and mortality rates of skin cancers are increasing and, therefore, pose a significant public health concern. Ultraviolet radiation (UVR) is the major etiologic agent in the development of skin cancers. UVR causes DNA damage and genetic mutations, which subsequently lead to skin cancer. A clearer understanding of UVR is crucial in the prevention of skin cancer. This article reviews UVR, its damaging effects on the skin and its relationship to UV immunosuppression and skin cancer. Several factors influence the amount of UVR reaching the earth’s surface, including ozone depletion, UV light elevation, latitude, altitude, and weather conditions. The current treatment modalities utilizing UVR (i.e. phototherapy) can also predispose to skin cancers. Unnecessary exposure to the sun and artificial UVR (tanning lamps) are important personal attributable risks. This article aims to provide a comprehensive overview of skin cancer with an emphasis on carefully evaluated statistics, the epidemiology of UVR-induced skin cancers, incidence rates, risk factors, and preventative behaviors & strategies, including personal behavioral modifications and public educational initiatives.
Background Several of the characteristic clinical features of photoaged skin, including wrinkling, are thought to be dependent on changes in the dermal matrix brought about by chronic sun exposure. Such changes include reductions in collagens I, III and VII, an increase in elastotic material in the reticular dermis and a marked reduction in the microfibrillar glycoprotein fibrillin. Objectives To examine whether type VI collagen, a microfibrillar collagen necessary for cell–cell and cell–matrix communication, is affected by the photoageing process. Methods Six healthy volunteers with moderate to severe photoageing were enrolled into the study. Immunohistochemistry and in situ hybridization histochemistry were used to examine the levels of type VI collagen in photoprotected and photoaged sites. Results In photoprotected skin, type VI collagen was concentrated in the papillary dermis immediately below the dermal–epidermal junction, around blood vessels, hair follicles and glandular structures. The distribution of type VI collagen was unchanged in photoaged skin, although we observed an increase in the abundance of the α3 chain of collagen VI in the upper papillary dermis, at its junction with the dermal–epidermal junction (P < 0·05). No alterations were observed for any α chain at the mRNA level. Conclusions These studies suggest that chronic sun exposure (photoageing) has little or no effect on either the distribution, abundance or levels of expression of type VI collagen in human skin. Thus, type VI collagen, unlike other matrix components so far studied, appears to be relatively unaffected by the photoageing process.