Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness

Skin ageing is divided into chronological ageing and photoageing due to the cumulative effects of solar ultraviolet radiation. It is, however, difficult to measure the degree of photoageing and chronological ageing in humans in vivo . Here, we have evaluated the usefulness of ultrasonography for measurement of chronological ageing and photoageing in vivo . Twenty megahertz ultrasonography was performed in 90 individuals (29 men, 61 women, age 18–94) to describe age-related changes in sun-exposed regions with different levels of sun exposure (dorsal and ventral forearm, forehead, ankle) and non-exposed buttock skin. Skin thickness and skin echogenicity in different layers of the dermis were measured in ultrasound images. Additionally, cutaneous photodamage was scored clinically. Age-related changes were dependent on body site as well as layer of the dermis. A progressive, age-related decrease in echogenicity of the upper dermis was found in sun-exposed regions (dorsal forearm, forehead), but not in moderately exposed regions (ventral forearm, ankle). In the buttock an increase in echogenicity was observed. The echogenicity of the lower dermis increased in all examined sites. Skin thickness increased with age in the forehead and buttock, but decreased in the extremity skin. Our findings show that photoageing causes a decrease in echogenicity in the upper dermis. In contrast, chronological ageing is associated with an increase in echogenicity in the lower dermis. Although both increases and decreases in skin thickness were observed in different anatomical regions, there was no general relationship between skin thickness and age. Dermal echogenicity was deemed valuable for in vivo study of chronological ageing and photoageing.     

Dowling Oration delivered at the Royal College of Physicians, London, Friday 5 June 1998. Retinoids: renaissance and reformation

There is confusion as to the cutaneous signs of ageing. For the most part the features of photoageing, namely actinic lentigines and wrinkling, are misinterpreted as features of ageing. Wrinkling is associated with a loss of collagens from the papillary dermis resulting from imperfect remodelling of the dermal extracellular matrix following sun exposure. Retinoids are either derivatives of vitamin A or synthetic ligands of nuclear retinoid receptors. Retinoid receptors, notably retinoic acid receptor gamma and retinoid X receptor alpha are present in human skin. Topically applied all-trans retinoic acid can repair and probably prevent photoageing of the skin by modulation of collagen synthesis in the dermis. There is emerging evidence that intrinsic ageing of the skin is also amenable to reversal by topical retinoids.     

Mechanisms of photodamage of the skin and its functional consequences for skin ageing

Chronic photodamage of the skin manifests itself as extrinsic skin ageing (photoageing) and photocarcinogenesis. DNA photodamage and UV-generated reactive oxygen species are the initial molecular events that lead to most of the typical histological and clinical manifestations of chronic photodamage of the skin. Knowledge of the UV-absorbing chromophores in the skin and of the molecular mechanisms leading to the unwanted effects of sun exposure provide a basis for the development of novel strategies for the prevention and repair of photoageing. This review provides an overview of the photochemistry of the major skin chromophores and their relationship to chronic photodamage.     

In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy

Background Skin ageing is a complex process due to intrinsic chronological factors (chronoageing) and extrinsic environmental factors. The primary extrinsic factor is cumulative ultraviolet (UV) exposure, and is therefore termed photoageing. The current standards for measuring cumulative sun damage are biopsy histology and skin microtopography. However, skin biopsies are too invasive for population studies and skin replicas render only superficial skin architecture data. Reflectance confocal microscopy (RCM) is a noninvasive imaging tool that allows for in vivo imaging of the skin at quasihistological resolution. Objectives To define and identify RCM features associated with chronological ageing and photoageing on the forearm in two age groups with different skin phototypes and to assess whether these results agree with previous findings. Methods We obtained RCM images of dorsal and volar nonlesional skin of the lower forearm of 75 individuals with skin Fitzpatrick phototypes I–III in two age groups (20–30 years and 50–60 years). From each participant and body site, 21 RCM features were assessed and statistically significant differences between the two age groups and different forearm sites determined. Results RCM enabled identification of changes in architecture, cell morphology and extracellular matrix (collagen) at the level of the epidermis, dermoepidermal junction and papillary dermis. Changes that were correlated with chronological ageing and which were aggravated on the UV‐exposed dorsal forearm were: loss of small skin furrows resulting in wider and less intersecting furrows; irregularity of the epidermal honeycomb pattern; irregularly distributed (mottled) pigmented keratinocytes/melanocytes; irregularity of the papillary rings and/or effacement of the rete ridges; and loss of thin collagen fibres and presence of collagen clods. Conclusion We have tested previously reported and new parameters for skin ageing evaluation by RCM, and identified 15 statistically significant RCM features that can be used to quantify ageing and photoageing in forearm skin noninvasively.     

The role of retinoids in the prevention and repair of aged and photoaged skin

Retinoids, either naturally occurring or synthetic, are defined by their ability to bind nuclear retinoid receptors of the steroid/thyroid superfamily. Their protean but key function in physiology is control of cellular proliferation and differentiation. Topical retinoids, namely tretinoin, have been proven to prevent and repair clinical features of photoageing; these processes are facilitated by an ability to prevent loss of collagen from, and stimulate new collagen formation in, the papillary dermis of sun-exposed skin. Emerging evidence indicates that intrinsic, chronological ageing of the skin shares several mechanistic features with photoageing. Indeed aged skin is characterized by retinoid sensitivity and is probably reparable by application of topical retinoids.     

How best to halt and/or revert UV-induced skin ageing: strategies, facts and fiction

Abstract:  Once considered mainly a cosmetic issue, photoageing research has long moved to the forefront of investigative dermatology. Besides obvious market pressures, increasing insight into the mechanistic overlap between UV-induced skin cancer and UV-induced skin ageing has contributed to this development. Also, as strategies that work to antagonize intrinsic skin ageing/senescence may also be exploited against photoageing (and vice versa!), it has become an important skin research challenge to dissect both the differences and the overlap mechanisms between these interwined, yet distinct phenomena. Finally, the current surge in putative 'antiageing' products, devices, and strategies – too many of which boldly promise to fight and/or repair the perils that come along with a lifetime spent in the sun in the absence of convincing evidence of efficacy – makes it particularly pertinent to critically review the available evidence to support often made antiageing claims. The current CONTROVERSIES feature, therefore, aimed to provide both guidance through, and critical voices in, the antiageing circus. Here, a panel of experts defines relevant key problems, points the uninaugurated to intriguing aspects of photoageing that one may not have considered before, highlights promising strategies for how best to halt and/or revert it, and spiritedly debates some controversially discussed approaches.     

Photoageing: mechanism, prevention and therapy

Photoageing is the superposition of chronic ultraviolet (UV)-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. It is triggered by receptor-initiated signalling, mitochondrial damage, protein oxidation and telomere-based DNA damage responses. Photodamaged skin displays variable epidermal thickness, dermal elastosis, decreased/fragmented collagen, increased matrix-degrading metalloproteinases, inflammatory infiltrates and vessel ectasia. The development of cosmetically pleasing sunscreens that protect against both UVA and UVB irradiation as well as products such as tretinoin that antagonize the UV signalling pathways leading to photoageing are major steps forward in preventing and reversing photoageing. Improved understanding of the skin's innate UV protective mechanisms has also given rise to several novel treatment concepts that promise to revolutionize this field within the coming decade. Such advances should not only allow for the improved appearance of skin in middle age and beyond, but also greatly reduce the accompanying burden of skin cancer.     

Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans

Summary Chronic sun exposure leads to structural and functional alterations in exposed skin. Photoageing is a process distinct from the changes taking place due to chronological ageing. Unique alterations in the dermal extracellular matrix occur as a result of photoageing and are responsible for many of these physiological changes taking place in sun-damaged skin. Accompanying the deposition of abnormal elastic tissue, or solar elastosis, are significant alterations in dermal glycosaminoglycans (GAGs). Accumulation of GAGs as a result of photoageing as demonstrated in both humans and animal models of photoageing seems almost paradoxical in view of the large amounts of GAGs present in the skin of newborns, making their skin well hydrated and supple, in sharp contrast to the weathered appearance of photoaged skin. We investigate the relative GAG content of photoaged skin using immunoperoxidase stains specific for hyaluronic acid and chondroitin sulphate, and determine the location of these GAGs using confocal laser scanning microscopy. Our results demonstrate significant increases in GAG staining in sun-damaged vs. sun-protected skin from the same individuals, as measured by computer-based image analysis. Furthermore, confocal laser scanning microscopy reveals that the increased dermal GAGs in sun-damaged skin are deposited on the elastotic material of the superficial dermis of photodamaged skin, and not between collagen and elastic fibres as in normal skin. The abnormal location of GAGs on these fibres may explain the apparent paradoxical weathered appearance of photodamaged skin despite increased GAGs.     

Receptors in skin ageing and antiageing agents

Skin ageing is an irreversible process during which ultrastructural and physiologic alterations happen. Dermatology has focused a lot of attention on the reversal of signs of ageing and photodamage, with the purposes of achieving cosmetic benefits and preventing photocancerogenesis. Recent advances in skin biology have clarified the mechanisms by which photoageing occurs and have given rise to new treatments to prevent and reverse this process. The understanding of the role of key receptors involved in the complex pathomechanism of skin ageing probably will lead to the development of the new therapeutic agents in the near future.     

Skin ageing

Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun‐exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies.     

A new surgical approach for the treatment of severe epithelial skin sun-induced damage

BACKGROUND: Cutaneous photoageing is a complex biological process affecting all layers of the skin. Skin damage resulting from intrinsic ageing and extrinsic photoageing may trigger skin cancer. In patients with advanced photoageing and/or diffuse actinic damage, local therapy is often inadequate and the possibility of combined therapy needs to be assessed. SUBJECTS: Here we report three cases of patients over 75 years of age with advanced diffuse epithelial skin damage of photoexposed areas consisting of several superficial actinic keratoses, ipermelanotic lesions and multiple skin cancers. METHODS: Neoplastic lesions and damaged skin were removed by superficial erbium laser ablation and the epidermis reconstructed with autologous epidermal sheets expanded in vitro from healthy cells obtained from unexposed areas of the body. RESULTS: Our initial studies show that this procedure is very effective in the short term for treating and preventing the UV-induced skin cancer and precancerous lesions, and also suggest good long-term control of the disease with very interesting aesthetic results.     

UVA‐1 exposure in vivo leads to an IL‐6 surge within the skin

UVA‐1 is a known promotor of skin ageing. Cytokines like IL‐1α, Il‐1β or TNF‐α, VEGF and IL‐6 orchestrate UV effects, and IL‐6 is furthermore an effector of UVA‐induced photoageing. We investigated how fractionated UVA‐1 doses influence the cytokine milieu and especially the IL‐6 levels in the skin in vivo. In a study with 35 participants, we exposed previously unirradiated human skin to three UVA‐1 irradiation regimes. Cytokine levels in interstitial skin fluid were measured up to 48 hours postexposure and compared to unirradiated control skin fluid. Our results show that IL‐6 levels increased significantly after UVA‐1 exposure at selected time points. The other candidates IL‐1α, Il‐1β or TNF‐α and VEGF show no significant response after UVA‐1 exposure in vivo. UVA‐1 thus raises selectively IL‐6 levels in vivo, a fact that underlines its role in photoageing and has potential implications for its modulatory effect on photoageing pathology.     

Increased expression of TRPV1 channel in intrinsically aged and photoaged human skin in vivo

Abstract:  Transient receptor potential vanilloid type 1 (TRPV1) is activated by various stimuli including capsaicin, heat and acid. While TRPV1 has been localized in the epidermis, little is known about the physiological role of TRPV1 in the skin, especially in skin ageing. In this study, we investigated the effect of acute UV irradiation on TRPV1 expression in human skin and the changes in TRPV1 mRNA and protein in intrinsic ageing and photoageing using human sun-protected (upper inner arm) and sun-exposed (forearm) skin of young and elderly subjects.
Western blot analysis of UV-irradiated young buttock skin revealed that the expression of TRPV1 protein was increased at 24 h (2.3-fold) and 48 h (2.4-fold) after UV irradiation. Real-time PCR analysis also showed that the mRNA level of TRPV1 was augmented by 2.4-fold at 4 h after UV irradiation. TRPV1 protein was expressed at higher levels by 2.6-fold in the sun-protected skin of the elderly subjects than in that of young people according to western blotting, real-time PCR analysis and immunohistochemical staining. In addition, the photoaged skin of elderly showed increased expression of TRPV1 mRNA and protein compared with that of the sun-protected skin of the same individuals. Also, we found increased expression of TRPV1 in nerve fibres of elderly persons using double staining of TRPV1 and nerve fibres.
Based on the above results, our data suggest that the expression of TRPV1 is affected by both the intrinsic ageing and photoageing processes.     

Clinical and biological impact of the exposome on the skin

The skin exposome is defined as the totality of environmental exposures over the life course that can induce or modify various skin conditions. Here, we review the impact on the skin of solar exposure, air pollution, hormones, nutrition and psychological factors. Photoageing, photocarcinogenesis and pigmentary changes are well-established consequences of chronic exposure of the skin to solar radiation. Exposure to traffic-related air pollution contributes to skin ageing. Particulate matter and nitrogen dioxide cause skin pigmentation/lentigines, while ozone causes wrinkles and has an impact on atopic eczema. Human skin is a major target of hormones, and they exhibit a wide range of biological activities on the skin. Hormones decline with advancing age influencing skin ageing. Nutrition has an impact on numerous biochemical processes, including oxidation, inflammation and glycation, which may result in clinical effects, including modification of the course of skin ageing and photoageing. Stress and lack of sleep are known to contribute to a pro-inflammatory state, which, in turn, affects the integrity of extracellular matrix proteins, in particular collagen. Hormone dysregulation, malnutrition and stress may contribute to inflammatory skin disorders, such as atopic dermatitis, psoriasis, acne and rosacea.     

Effects of ageing on dermal echogenicity

Background/aims: Changes in the dermis associated with ageing can be detected by high-frequency skin ultrasonography. In photoaged skin, this technique shows a subepidermal low echogenic band (SLEB) that is probably an ultrasound manifestation of elastosis and oedema in the papillary dermis. Since some authors found an association between age and SLEB thickness or its echogenicity on exposed sites, it has been proposed to use these parameters to quantify skin photoageing.
Methods: To determine whether SLEB can be used as a quantitative marker of ageing, its prevalence was determined on forearm skin in a group of 55 individuals (age 18–57 years). The size of SLEB has been measured by quantifying the number of low echogenic pixels in the subepidermal area, which is an accurate method for assessing SLEB severity.
Results: The prevalence of SLEB increased with age, but SLEB was also present in young subjects. The echogenicity of the subepidermal area did not show any age dependence. However, when a ratio of echogenicity between upper and lower dermis was calculated, a linear dependence on age was found.
Conclusions: This study indicates that skin echogenicity measured as a ratio between the upper and lower dermis may be used to objectively estimate photoageing.     

Management of skin ageing: how to combine cosmetic procedures

Skin ageing may be physiological and/or a result of photoageing. To provide comprehensive management of ageing skin, it is essential to make a thorough diagnosis before any therapeutic decision is made. The most appropriate treatment(s) may then be offered to the patient. This comprehensive approach to care requires knowledge of the mechanisms of skin ageing and the advantages and drawbacks of the different therapeutic approaches available, in order to arrive at the best therapeutic strategy and to meet patient expectations. There are very many different therapeutic approaches, and in the context of work by a group of European experts it seems appropriate to propose a therapeutic strategy for the overall management of skin ageing to help dermatologists in their daily work with patients. This therapeutic strategy is based both on an analysis of the literature and the personal experience of the experts.