Intrinsic Skin Aging Research Articles

Airborne Particle Exposure and Extrinsic Skin Aging

For decades, extrinsic skin aging has been known to result from chronic exposure to solar radiation and, more recently, to tobacco smoke. In this study, we have assessed the influence of air pollution on skin aging in 400 Caucasian women aged 70-80 years. Skin aging was clinically assessed by means of SCINEXA (score of intrinsic and extrinsic skin aging), a validated skin aging score. Traffic-related exposure at the place of residence was determined by traffic particle emissions and by estimation of soot in fine dust. Exposure to background particle concentration was determined by measurements of ambient particles at fixed monitoring sites. The impact of air pollution on skin aging was analyzed by linear and logistic regression and adjusted for potential confounding variables. Air pollution exposure was significantly correlated to extrinsic skin aging signs, in particular to pigment spots and less pronounced to wrinkles. An increase in soot (per 0.5 × 10(-5) per m) and particles from traffic (per 475 kg per year and square km) was associated with 20% more pigment spots on forehead and cheeks. Background particle pollution, which was measured in low residential areas of the cities without busy traffic and therefore is not directly attributable to traffic but rather to other sources of particles, was also positively correlated to pigment spots on face. These results indicate that particle pollution might influence skin aging as well.

Proteomic profiling reveals a catalogue of new candidate proteins for human skin aging

Studies of skin aging are usually performed at the genomic level by investigating differentially regulated genes identified through subtractive hybridization or microarray analyses. In contrast, relatively few studies have investigated changes in protein expression of aged skin using proteomic profiling by two-dimensional (2-D) gel electrophoresis and mass spectrometry, although this approach at the protein level is suggested to reflect more accurately the aging phenotype. We undertook such a proteomic analysis of intrinsic human skin aging by quantifying proteins extracted and fluorescently labeled from sun-protected human foreskin samples pooled from 'young' and 'old' men. In addition, we analyzed these candidate gene products by 1-D and 2-D western blotting to obtain corroborative protein expression data, and by both real-time PCR (RT-PCR) and microarray analyses to confirm expression at the mRNA level. We discovered 30 putative proteins for skin aging, including previously unrecognized, post-translationally regulated candidates such as phosphatidyl-ethanolamine binding protein (PEBP) and carbonic anhydrase 1 (CA1).

Aquaporin‐3 gene and protein expression in sun‐protected human skin decreases with skin ageing

Aquaporin 3 (AQP3) is a protein implicated in skin hydration. AQP3 null mice have relatively dry skin, reduced skin elasticity, and delayed recovery of barrier function after removal of the stratum corneum which is also present in skin of old people. A feature of skin aging is the change in both water content and barrier function of the skin. We investigated the expression of aquaporin 3 in non sun-exposed human skin, normal human keratinocytes and fibroblasts from different age groups to further understand the relationship between AQP3 and intrinsic skin aging. We investigated the expression of aquaporin3 (AQP3) in normal human skin, normal human epidermal keratinocytes (NHEK) and skin fibroblast of different ages by immunohistochemistry, immunocytochemistry, the reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. The samples were derived from 60 patients of varying ages: <20 years of age, 30-45 years and >60 years of age. Twenty skin biopsies, 6 for keratinocyte/fibroblast cultures, were taken from each age group. AQP3 decreased with increasing age in both skin and NHEK samples. We demonstrated significant differences in AQP3 expression between the 3 age groups (P < 0.05). In fibroblasts, AQP3 expression levels were significantly lower in the >60 year olds compared to 30-45 year olds (P < 0.05) and <20 year olds (P < 0.05), there was no significant difference between the two younger groups (P > 0.05). AQP3 may be involved in the intrinsic aging process of non sun-exposed human skin.

Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes

Extrinsic skin ageing or 'photoageing', as opposed to intrinsic skin ageing, is the result of exposure to external factors, mainly ultraviolet irradiation. Glycosaminoglycans (GAG) and particularly hyaluronic acid (HA) are major components of the cutaneous extracellular matrix involved in tissue repair. However, their involvement in extrinsic skin ageing remains elusive. In this study, we investigated the expression of HA and its metabolizing enzymes in photoexposed and photoprotected human skin tissue specimens, obtained from the same patient. Total GAG were isolated, characterized using specific GAG-degrading enzymes and separated by electrophoresis on cellulose acetate membranes and polyacrylamide gels. Quantitation of HA in total GAG was performed using ELISA. Gene expression of hyaluronan synthases (HAS), hyaluronidases (HYAL) and HA receptors CD44 and receptor for HA-mediated motility (RHAMM) was assessed by RT-PCR. We detected a significant increase in the expression of HA, of lower molecular mass, in photoexposed skin as compared with photoprotected skin. This increase was associated with a significant decrease in the expression of HAS1 and an increase in the expression of HYAL1-3. Furthermore, the expression of HA receptors CD44 and RHAMM was significantly downregulated in photoexposed as compared with photoprotected skin. These findings indicate that extrinsic skin ageing is characterized by distinct homoeostasis of HA. The elucidation of the role of HA homoeostasis in extrinsic skin ageing may offer an additional approach in handling cutaneous ageing.

Liver X receptor β: maintenance of epidermal expression in intrinsic and extrinsic skin aging

Aging in human skin is the composite of time-dependent intrinsic aging plus photoaging induced by chronic exposure to ultraviolet radiation. Nuclear hormone receptors coordinate diverse processes including metabolic homeostasis. Liver X receptor β (LXRβ) is a close human homologue of daf-12, a regulator of nematode longevity. LXRβ is positively regulated by sirtuin-1 and resveratrol, while LXRβ-null mice show transcriptional profiles similar to those seen in aged human skin. In these studies, we examined LXRβ expression in aged and photoaged human skin. Volunteers were recruited to assess intrinsic aging and photoaging. Epidermal LXRβ mRNA was examined by in situ hybridization while protein was identified by immunofluorescence. No significant changes were observed in either LXRβ mRNA or protein expression between young and aged volunteers (mRNA p = 0.90; protein p = 0.26). Similarly, LXRβ protein expression was unaltered in photoaged skin (p = 0.75). Our data therefore suggest that, while not playing a major role in skin aging, robust cutaneous expression implies a fundamental role for LXRβ in epidermal biology.

Skin atrophy in cytoplasmic SOD-deficient mice and its complete recovery using a vitamin C derivative

Intrinsic skin ageing is characterized by atrophy and loss of elasticity. Although the skin hypertrophy induced by photoageing has been studied, the molecular mechanisms of skin atrophy during ageing remain unclear. Here, we report that copper/zinc superoxide dismutase (CuZn-SOD)-deficient mice show atrophic morphology in their skin. This atrophy is accompanied by the degeneration of collagen and elastic fibers, and skin hydroxyproline is also significantly reduced in deficient mice. These imply that the dysfunction of collagen and elastin biosynthesis are involved in the progression of skin thinning. Furthermore, transdermal administration of a vitamin C derivative which can permeate through the membrane, completely reversed the skin thinning and deterioration of collagen and elastin in the mutant mice. These indicate that the vitamin C derivative is a powerful agent for alleviating skin ageing through regeneration of collagen and elastin. The CuZn-SOD-deficient mice might be applicable to evaluation of therapeutic medicines against skin ageing.

The SCINEXA: A novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing

Background Studies on the pathogenesis of skin ageing as well as efficacy testing of cosmetic and aesthetic measures to prevent or reverse skin ageing require – as an easy to use method – a validated non-invasive clinical score, which allows to simultaneously assess and differentiate between intrinsic (=chronological) and extrinsic (=photo-) skin ageing. Such an ideal score, however, does currently not exist. Objectives We developed a novel skin ageing score ‘SCINEXA’ comprising 5 items indicative of intrinsic and 18 items highly characteristic of extrinsic skin ageing. These items were used to define an index (index discr) that allowed differentiating between intrinsic versus extrinsic skin ageing. In order to validate the ‘SCINEXA’, we asked whether it can be used to discriminate regular sunbed users, which have been chronically exposed to ultraviolet radiation and thus are prone to photoageing, from non-sunbed users, which were considered paradigmatic for intrinsic skin ageing. Methods For this purpose, 58 non-sunbed users and 16 regularly sunbed users were assessed. In addition to the clinical examination of the 23 score items potential confounders were considered by questionnaire. Results By employing the index discr, we were able to classify 92% of all study subjects correctly as sunbed or non-sunbed users. Specifically, an index above 2 was associated with sunbed use and thus extrinsic skin ageing, whereas an index below 2 indicated intrinsic skin ageing. Conclusion The novel ‘SCINEXA’ is suitable for the simultaneous assessment of intrinsic and extrinsic skin ageing.

Deregulation of versican and elastin binding protein in solar elastosis

Several changes in skin appearance including loss of elasticity and wrinkle formation are associated with alterations in the composition of the dermal extracellular matrix. They are induced by intrinsic aging or by environmental factors such as UV light referred to as photoaging. A general characteristic in the histology of photoaged skin is the accumulation of elastotic material suggesting impaired formation and/or massive breakdown of elastic fibres. In order to shed light on some of the underlying mechanisms we tracked two of the major players in elastic fibre formation in different skin conditions: EBP (elastin binding protein), a regulator of elastic fibre assembly and VER (versican), a component of functional elastic fibres as well as non-functional elastotic material. Using quantitative RT-PCR on skin biopsies we found that the expression levels of VER and EBP were unaltered during intrinsic skin aging. Upon acute UV stress however, VER and EBP showed different regulation patterns: VER mRNA increased after 6 h and was further up-regulated until 24 h. The EBP mRNA by contrast was reduced after 6 h but showed massive induction at 24 h after acute UV stress. In chronically sun-exposed skin, VER protein was accumulated similar to elastotic material in the extracellular space, whereas its mRNA level was consistently reduced compared to sun-protected skin. The EBP mRNA by contrast showed slightly increased expression levels in the sun-exposed area compared to its sun-protected counterpart. Based on these data we propose a model which may help to explain parts of the mechanisms leading to the formation of elastotic masses. We further hypothesize that the presence of elastotic material triggers some yet unknown feedback mechanism(s) resulting in altered expression patterns of VER and EBP in chronically sun-exposed skin.

Cytokeratin-related loss of cellular integrity is not a major driving force of human intrinsic skin aging

The contribution of extracellular matrix components to intrinsic skin aging has been investigated thoroughly, however, there is little information as to the role of the cytoskeletal proteins in this process. Therefore, we compared the expression of the constituents of the cytoskeleton, keratins 1–23 (K1-K23) as well as junction-plakoglobin (JUP), α-tubulin (TUBA), and β-actin (ACTB) in human foreskins of both young (mean 6.4 years) and aged (mean 54.3 years) individuals. By applying RNA expression analysis to intrinsically aged human skin, we demonstrated that the mRNA levels of the genes for K1, K3, K4, K9, K13, K15, K18, K19 and K20 are downregulated in aged skin, K5 and K14 are unchanged, and K2, K16 and K17 are upregulated in aged skin. The mRNA data were confirmed on the protein level. This diverse picture is in contrast to other cytoskeletal proteins including components of the desmosome (JUP), microtubuli (TUBA) and microfilaments (ACTB) – often regarded as house-keeping genes – that were all reduced in aged skin. These cytoskeletal features of intrinsic aging highlight the importance of the cellular compartment in this process and demonstrate that special attention has to be given to RNA as well as protein normalization in aging studies.

Expression profiling of senescent-associated genes in human dermis from young and old donors. Proof-of-concept study

It is often described that it is difficult to really discriminate the cause of intrinsic skin aging. The aim of this study was to compare the profiles of expression of senescence-associated genes in biopsies of dermis from young and old human donors. TGF-beta1 was up-regulated in the dermis of old donors as well as the TGF-beta1-regulated genes. The anti-oxidant enzymes Selenium-dependent Glutathione peroxidase and Glutatione S-Transferase Theta 1 were also up-regulated in old dermis as well as Tumor Necrosis Factor Receptor Superfamily 1A. None of these genes had altered expression level in skin fibroblasts embedded in a collagen matrix and exposed to sublethal doses of UVB, suggesting their involvement in intrinsic aging. This study represents a proof-of-concept of larger whole transcriptome studies where all avenues should be used to subtract changes in gene expression due to extrinsic aging from changes potentially due to intrinsic aging.

Association of retinaldehyde (RAL) and hyaluronic acid fragments (HAF): Effects on intrinsic skin aging

Association of retinaldehyde (RAL) and hyaluronic acid fragments (HAF): Effects on intrinsic skin aging

The skin as a mirror of the ageing process in the human organism – results of the ageing research in the German National Genome Research Network 2

Intrinsic human skin ageing is influenced by the individual genetic predisposition and reflects degradation processes of the body. Hormones are decisively involved in intrinsic ageing with reduced secretion of pituitary, adrenal glands, and gonads, which leads to characteristic body and skin phenotypes. A number of advances were recently made in understanding skin ageing mechanisms and major molecular changes, especiallly of the extracellular matrix, were identified. Gene expression patterns compatible with mitotic misregulation and alterations in intracellular transport and metabolism were identified in fibroblasts of ageing humans and humans with progeria. Age‐associated changes of extracellular matrix of the skin correlate well with changes been detected in the extracellular matrix of other organs of the human body. Within the National Genome Research Network 2 (NGFN‐2) in Germany, the explorative project ‘Genetic etiology of human longevity’ targets the identification of age‐related molecular pathways. For this purpose, skin models of ageing are used. Expression profiling employing cDNA microarrays from known and novel genes and RT‐PCR are employed for gene detection and confirmation. Among the potential candidate genes several interesting target genes have been identified. The evaluation of ageing‐associated genes in skin models will facilitate the understanding of global molecular ageing mechanisms in the future.

Heat shock proteins in the skin

Heat shock proteins (hsp) are expressed in all cells and organisms. Their expression is induced by heat shock (temperatures above 42 degrees C) and other forms of pathophysiological stress. Elevated levels of hsp protect cells from further stress exposure. Hsp are expressed intracellularly. They are highly conserved throughout evolution indicating hsp being necessary for survival under potentially harmful environmental conditions. Hsp are divided into families according to their molecular weight. The majority of hsp function as molecular chaperones. Chaperone function is characterized by binding to other proteins and mediating their folding, transport and interaction with other molecules. In human epidermis hsp are abundantly expressed and have been linked with functions in cell differentiation and photobiology. Recent research has mainly focused on the 27 and 72 kD hsp that are constitutively expressed in human keratinocytes. ultraviolet radiation (UV)-induced cell death and sunburn cell formation can be inhibited by previous heat shock exposure and UV itself can induce hsp expression. The expression of the 27 kD hsp (hsp27) in epidermal keratinocytes in situ and in culture correlates with differentiation. Expression of hsp27 increases simultaneously with keratinocyte differentiation. For that reason, hsp27 is described as a marker of epidermal differentiation. Changes in the expression and inducibility of hsp have been linked with ageing. In the skin, recent data indicate that hsp72 expression remains remarkably stable with intrinsic ageing. In contrast, levels of hsp27 have been found to be elevated in sun-protected aged skin indicating a link between hsp27 expression and age-dependent epidermal alterations. Regulation of hsp can be modified by pharmacological intervention and the development of safe topical and systemic treatments for the prevention of skin damage and disorders of keratinocyte differentiation can be expected for the future.

Unveiling the molecular basis of intrinsic skin aging1

The process of skin aging is a combination of an extrinsic and intrinsic aspect, and knowing the molecular changes underlying both is a prerequisite to being able to effectively counter it. However, despite its importance for a deeper understanding of skin aging as a whole, the process of intrinsic skin aging in particular has barely been investigated. In this study, the molecular changes of intrinsic skin aging were analyzed by applying 'Serial Analysis of Gene Expression' (SAGE(TM)) to skin biopsies of young and aged donors. The analysis resulted in several hundred differentially expressed genes with varying statistical significance. Of these, several genes were identified that either have never been described in skin aging before (e.g. APP) or have no identified function, e.g. EST sequences. This is the first time that intrinsic skin aging has been analyzed in such a comprehensive manner, offering a new and partially unexpected set of target genes that have to be analyzed in more detail in terms of their contribution to the skin aging process.

Novel Aspects of Intrinsic and Extrinsic Aging of Human Skin: Beneficial Effects of Soy Extract¶

ABSTRACTBiochemical and structural changes of dermal connective tissue substantially contribute to the phenotype of aging skin. To study connective tissue metabolism with respect to ultraviolet (UV) exposure, we performed an in vitro (human dermal fibroblasts) and an in vivo complementary DNA array study in combination with protein analysis in young and old volunteers. Several genes of the collagen metabolism such as Collagen I, III and VI as well as heat shock protein 47 and matrix metalloproteinase‐1 are expressed differentially, indicating UV‐mediated effects on collagen expression, processing and degradation. In particular, Collagen I is time and age dependently reduced after a single UV exposure in human skin in vivo. Moreover, older subjects display a lower baseline level and a shorter UV‐mediated increase in hyaluronan (HA) levels. To counteract these age‐dependent changes, cultured fibroblasts were treated with a specific soy extract. This treatment resulted in increased collagen and HA synthesis. In a placebo‐controlled in vivo study, topical application of an isoflavone‐containing emulsion significantly enhanced the number of dermal papillae per area after 2 weeks. Because the flattening of the dermal‐epidermal junction is the most reproducible structural change in aged skin, this soy extract appears to rejuvenate the structure of mature skin.

Increased expression of 14-3-3ɛ protein in intrinsically aged and photoaged human skin in vivo

Skin aging is a complicated process associated with the passage of time and environmental exposure, especially to UV light. This aging phenomenon is related to alterations in various cellular mechanisms, such as changes in apoptosis, perturbations to cellular signaling, and an increased genetic instability. In this study, we investigated changes of proteins involved in intrinsic aging by the proteomic analysis of human sun-protected (upper inner arm) young and aged dermis. One of the proteins upregulated in aged dermis was identified as 14-3-3ɛ. This protein is an isoform of 14-3-3 protein, which is involved in cellular processes like signal transduction, cell cycle arrest, and apoptosis. 14-3-3ɛ is consistently found to be upregulated in the sun-protected dermis of aged skin, by Western blotting and immunohistochemical staining. In addition, we demonstrate that the expression of 14-3-3ɛ is further upregulated in the sun-exposed (photodamaged) dermis, and that the UV irradiation of young skin significantly upregulates 14-3-3ɛ in vivo. Our results suggest the possibility that the cellular processes related to 14-3-3ɛ protein play an important role in the photoaging and intrinsic aging of human skin.

Novel Aspects of Intrinsic and Extrinsic Aging of Human Skin: Beneficial Effects of Soy Extract¶

Biochemical and structural changes of the dermal connective tissue substantially contribute to the phenotype of aging skin. To study connective tissue metabolism with respect to ultraviolet (UV) exposure, we performed an in vitro (human dermal fibroblasts) and an in vivo complementary DNA array study in combination with protein analysis in young and old volunteers. Several genes of the collagen metabolism such as Collagen I, III and VI as well as heat shock protein 47 and matrix metalloproteinase-1 are expressed differentially, indicating UV-mediated effects on collagen expression, processing and degradation. In particular, Collagen I is time and age dependently reduced after a single UV exposure in human skin in vivo. Moreover, older subjects display a lower baseline level and a shorter UV-mediated increase in hyaluronan (HA) levels. To counteract these age-dependent changes, cultured fibroblasts were treated with a specific soy extract. This treatment resulted in increased collagen and HA synthesis. In a placebo-controlled in vivo study, topical application of an isoflavone-containing emulsion significantly enhanced the number of dermal papillae per area after 2 weeks. Because the flattening of the dermal-epidermal junction is the most reproducible structural change in aged skin, this soy extract appears to rejuvenate the structure of mature skin.

The role of reactive oxygen species and antioxidants in dermatology

2500 million years ago, oxygen accumulated in the Earth's atmosphere as a result of the evolution of algae capable of photosynthesis. The enormous benefit of oxygen utilization for obtaining energy led to the rapid expansion of aerobic organisms. However, the high reactivity of the oxygen was coupled with the danger of oxidation of important cell components. Roughly 2% of electrons are lost during electron transport in mitochondrial membranes, leading to the formation of reactive oxygen species. Some of these are free radicals, which are defined as atoms or molecules with an unpaired electron, like superoxide anion or the hydroxyl radical. These molecules are extremely chemically reactive and short‐lived. Other reactive molecules such as singlet oxygen and hydrogen peroxide are not free radicals, but are as reactive and capable of initiating oxidative reactions. Together, these molecules are calledreactive oxygen species.Cells have evolved various antioxidant and repair systems for protection against metabolically produced reactive oxygen species. Antioxidant enzymes include superoxide dismutase, catalase, glutathione reductase and glutathione peroxidases, which collectively destroy superoxide, hydrogen peroxide and lipid hydroperoxides. Nonenzymatic small‐molecular‐weight antioxidants are no less important. They build up an effective antioxidant network, which includes glutathione (GSH) and ascorbic acid (vitamin C) in the aqueous phase, and tocopherol (vitamin E) and ubiquinol (coenzyme Q) in the lipid phase. Nevertheless, these systems can be overwhelmed in times of increased oxidative stress, e.g. high metabolic demands or outside forces such as sunlight, smoking or pollution. This then results in oxidative damage of cell components, like proteins, lipids or DNA. Good examples for the consequences of repeated oxidative stress to skin are the aging process and aging‐associated skin cancers. There is much evidence that skin aging can be subdivided into intrinsic and extrinsic skin aging. Reactive oxygen species are not only involved in the metabolically induced intrinsic type of skin aging. Various exogenous sources of oxidative stress, in particular ultraviolet (UV)‐irradiation, are believed to be responsible for the extrinsic type of skin aging, therefore also termed photoaging. Regarding photocarcinogenesis, shorter wavelength UVB light is important for tumour initiation, but UVA light, which generates more oxidative stress, predominantly causes tumour promotion in nonmelanoma skin cancer. It therefore seems reasonable from various standpoints to increase levels of protective antioxidant systems. One feasible approach is to increase low‐molecular‐weight antioxidants through a diet rich in fruits and vegetables, systemic supplements or by direct topical application. Indeed, various invitro and experimental animal studies have proved that dietary low‐molecular‐weight antioxidants or supplements, especially ascorbate and tocopherol as well as polyphenols and flavonoids, exert protective effects against oxidative stress. However, controlled long‐term studies on the efficacy of low‐molecular‐weight antioxidants in the prevention or treatment of skin aging in humans are still lacking.

Retinoic acid receptor α expression and cutaneous ageing

Intrinsic ageing of human skin is a subtle and gradual process that demonstrates few clinical or histological features until old age (>70 years). Initial work indicates that aged skin is “retinoid sensitive” but there is little data on the role of retinoic acid receptors (RARs) or retinoid X receptors (RXRs) in skin ageing. As nuclear retinoid receptors have been implicated in ageing in rodents, we studied the distribution of these receptors in intrinsically aged as compared to young, photoprotected human skin. We found that intrinsic ageing of skin in vivo is accompanied by significant increases of RARα mRNA and protein whereas other isoforms show no alteration with age. In vitro transfection of COS-1 cells with the RARα gene induces expression of matrix metalloproteinase-1 (MMP-1), an enzyme known to play an active role in remodelling of the dermis in intrinsically aged and photoaged skin. Furthermore, addition of all- trans retinoic acid (RA) to cultures of RARα-transfected COS-1 cells diminishes RARα and returns levels of MMP-1 to those approaching baseline. These results demonstrate that intrinsic ageing of human skin is accompanied by significant elevation in the content of RARα and that over-expression of RARα influences expression of MMP-1, an important mediator of skin ageing.

Retinoic acid receptor $alpha; expression and cutaneous ageing

Intrinsic ageing of human skin is a subtle and gradual process that demonstrates few clinical or histological features until old age (>70 years). Initial work indicates that aged skin is “retinoid sensitive” but there is little data on the role of retinoic acid receptors (RARs) or retinoid X receptors (RXRs) in skin ageing. As nuclear retinoid receptors have been implicated in ageing in rodents, we studied the distribution of these receptors in intrinsically aged as compared to young, photoprotected human skin. We found that intrinsic ageing of skin in vivo is accompanied by significant increases of RARα mRNA and protein whereas other isoforms show no alteration with age. In vitro transfection of COS-1 cells with the RARα gene induces expression of matrix metalloproteinase-1 (MMP-1), an enzyme known to play an active role in remodelling of the dermis in intrinsically aged and photoaged skin. Furthermore, addition of all-trans retinoic acid (RA) to cultures of RARα-transfected COS-1 cells diminishes RARα and returns levels of MMP-1 to those approaching baseline. These results demonstrate that intrinsic ageing of human skin is accompanied by significant elevation in the content of RARα and that over-expression of RARα influences expression of MMP-1, an important mediator of skin ageing.