International Journal of Cosmetic Science, 2008, 30, 313322

Review Article

A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part I: Cellular and molecular perspectives of skin ageing
T. M. Callaghan1 and K.-P. Wilhelm
proDERM Institute for Applied Dermatological Research, Kiebitzweg 2, 22869 Schenefeld/Hamburg, Germany

Received 8 February 2008, Accepted 21 April 2008

Keywords: molecular skin ageing, oxidative stress, ROS

Synopsis The ageing process is noticeable within all organs of the body and manifests itself visibly in the skin. Skin ageing is inuenced by several factors including genetics, environmental exposure, hormonal changes and metabolic processes. Together these factors lead to cumulative alterations of skin structure, function and appearance. The functioning of the central nervous, immune, endocrine and cardiovascular systems, as well as the skin is also impaired with age. Chronologically, aged skin is thin, relatively attened, dry and unblemished, with some loss of elasticity and age-related loss of architectural regularity. General atrophy of the extracellular matrix is reected by a decrease in the number of broblasts. Reduced levels of collagen and elastin, with impaired organization are primarily because of decreased protein synthesis affecting types I and III collagen in the dermis, with an increased breakdown of extracellular matrix proteins. Oxidative stress is considered of
Correspondence: K.-P. Wilhelm, proDERM Institute for Applied Dermatological Research, Kiebitzweg 2, 22869 Schenefeld/Hamburg, Germany. Tel.: +49 40 839 358 11/17; fax: +49 40 839 358 39; e-mail: sleuschner@ proderm.de
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primary importance in driving the ageing process. The original free radical theory of ageing purported that the molecular basis of ageing was derived from a lifetime accumulation of oxidative damage to cells resulting from excess reactive oxygen species (ROS) produced as a consequence of aerobic metabolism. Although the skin possesses extremely efcient anti-oxidant activities, during ageing, ROS levels rise and anti-oxidant activities decline. The ROS are necessary in multiple MAP kinase pathways and the induction of AP-1, in turn, up-regulates expression of matrix-metalloproteinases providing a plausible mechanism for the increased collagen degradation in aged human skin. sume Re Le processus de vieillissement est perceptible sur tous les organes du corps et se manifeste clairement au niveau de la peau. Le vieillissement de la e par plusieurs facteurs comme peau est inuence ne tique, lexposition environnementale, les la ge canismes me tabolivariations hormonales, les me ` rents facteurs conduisent a ques. Ensemble, ces diffe rations cumulatives de la structure de la des alte peau, de sa fonction et de son apparence. Le fonc` me nerveux central, immunitionnement du syste taire, endocrinien et cardio-vasculaire est, comme par la ge. La peau a ge e est ne, la peau, touche ` che et sans de che e, se faut avec relativement rela

Present address: DermPharCos, Witts Park 16, 22587 Hamburg, Germany.

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lasticite et une perte de sa re gularite une perte de ne rale de la matrice architecturale. Une atrophie ge extracellulaire se traduit par une diminution du nombre de broblastes. La diminution des teneurs ` ne et e lastine avec une perte de leur en collage ` une dimiorganisation est en premier lieu due a ` se prote inique affectant les nution de la synthe ` nes de type I et III dans le derme, ainsi qua ` collage te rioration des prote ines de la matrice une de ` re que le stress oxydatif extracellulaire. On conside ` re importance dans le me canisme de est de premie orie du vieillissement, base e vieillissement. La the cusur les radicaux libres, stipule que la base mole laire du vieillissement sexplique par laccumulation, au cours de la vie, des dommages oxydatifs ` s de production de ROS s aux cellules par exce cause quence du me tabolisme ae robie. Bien comme conse ` de une activite anti-oxydante que la peau posse mement efcace durant le vieillissement, les extre s antiteneurs en ROS augmentent et les activite cessaires oxydantes diminuent. Les ROS sont ne dans les multiples cheminements de la kinase MAP gule lexpreset linduction de lAP-1 en retour re canisme plausible sion des MMPs fournissant un me te rioration pour expliquer laugmentation de la de ` ne des peaux humaines a ge es. du collage Introduction Society today still continues to extol a youthful appearance, despite ageing being a fact of life. The ageing process is noticeable within all organs of the body and manifests itself visibly in the skin. In addition, the functioning of the central nervous, immune, endocrine and cardiovascular systems, as well as the skin is also impaired with age. Impairment of the adaptive and homoeostatic or homoeodynamic mechanisms leads to susceptibility of environmental or internal stresses with increasing probability of disease and death. A number of theories of primary ageing independent of disease have been put forward over the last decades; however, it has also been suggested that ageing is simply the convergence of various diseases. Without an underlying or primary ageing process, the risk of death would remain constant or even decrease with old age as those individuals best able to avoid disease survive. However, the risk of death increases with chronological age. From the cellular perspective, there are several mechanisms considered to trigger the primary

ageing process and therefore contribute to agerelated changes in adaptive and pharmacological responses including oxidative stress, mitochondrial dysfunction, telomere shortening and various genetic mechanisms. Oxidative stress Substantial evidence exists to support that ageing is associated with, though more likely, the consequence of free radical damage by various endogenous reactive oxygen species (ROS) the original free radical theory of ageing being proposed by Harman [1, 2]. The role of ROS in ageing is thought to explain why animals with higher metabolic rates have shorter life spans [35], though this has been criticized by Olshansky and others [68] supporting the theory for metabolic stability. ROS include superoxide and hydroxyl radicals and other activated forms of oxygen such as hydrogen peroxide and singlet oxygen. The primary sites of production of ROS are the mitochondria and other major sources of ROS include phagocytosis, prostaglandin synthesis, cytochrome P450 enzymes, non-enzymatic reactions of oxygen and ionizing radiation. Enzymes that minimize oxidative injury include superoxide dismutase, catalase, glutathione peroxidase, glutathione transferases, peroxidases and thiol-specic anti-oxidant enzymes. These, together with a plethora of low-molecular weight compounds, e.g. ascorbate, glutathione, b-carotene, a-tocopherol, uric acid and bilirubin act as free radical scavengers [911]. Ageing is associated with changes in the molecular structure of DNA, proteins, lipids, and prostaglandins all markers of oxidative stress, though all changes are not because of oxidation only; there are other pathways also including spontaneous errors, other protein modications etc. [12, 13]. The accumulation of these molecular changes, particularly in proteins, constitutes the basis of cell ageing. However, it is also recognized that ROS play a role in normal signalling processes and that their generation is essential to maintain homoeostasis and cellular responsiveness [14]. Role of mitochondria Mitochondria are both producers and targets of oxidative stress thus forming the basis for the mitochondrial theory of ageing. Within mitochondria,

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accumulation of somatic mutations of mitochondrial DNA, induced by exposure to ROS, leads to errors in the mitochondrial DNA-encoded polypeptides and subsequent defective electron transfer activity and oxidative phosphorylation. With advancing age, the activity of the mitochondrial respiratory system and its constituent enzymes, notably cytochrome-C oxidase, in a range of tissues including skeletal muscle, heart and liver declines and thus the integrity of the mitochondrial DNA in these tissues is also reduced [1520]. Cellular senescence and telomeres Diploid cells exhibit a limited proliferation potential. After a nite number of divisions, they enter a state of replication senescence with an arrest in cellular propagation. This number of divisions, known as the Hayick limit, has been postulated to determine the maximum lifespan of an organism [21]. One explanation for cells reaching this limit arises from telomeres, the repetitive DNA sequences at the end of linear DNA. Telomeres shorten slightly each time the cell divides (about 50200 bp per cell division). Depletion, or rather shortening of telomere DNA prohibits further cell division [22]. In several premature ageing conditions, tissues of a particular chronological age contain cells much closer to their programmed cell division limit than those from similarly aged normal individuals [22, 23]. Cells of the germ line, stem cells and some other normal diploid cells contain an enzyme called telomerase that replaces telomer DNA lost during cell division. The possibility of reversing cellular senescence by switching on a copy of the gene encoding the telomerase catalytic subunit into normal cells, thus turning on telomerase activity has been considered [2435]. This strategy may also increase the risk that cells become immortalized. The cellular senescence theory of ageing has limitations because organs, such as the brain, which consist mostly of non-dividing cells, still age [3639]. Apoptosis It is suggested that ageing is mainly associated with up-regulation of apoptosis. However, it is not clear whether age-related changes in the mechanism of apoptosis are a result of genetic programming or ageing processes such as oxidative stress [17, 40, 41].
2008 proDERM GmbH. Journal compilation

Diet Calorie restriction extends lifespan in yeast, Drosophila, worms, rodents and probably primates. Despite extensive work demonstrating the effectiveness of calorie restriction, the mechanism by which it extends lifespan is unclear. One hypothesis is that it slows metabolism and hence the production of ROS [4244]. Conversely, obesity supposedly speeds up the ageing process which is further exacerbated with smoking, though there is, as yet, no real evidence for this [44]. Genetics The role of genetically programmed ageing is controversial and evidence of a primary role for genetic programming includes observations that the lifespan of a given species is relatively xed and that human ageing has a hereditary component [45, 46]. In addition, single mutations in humans can produce premature ageing syndromes and altered expression of single genes may increase maximum lifespan in lower organisms [4648]. However, a rational evolutionary principle makes the possibility of genetic determination of ageing less likely. Some genes will inuence longevity (gerontogenes) through responses to the underlying ageing processes or disease susceptibility [48, 49]. In humans, genetic variations associated with longevity are essentially those associated with disease susceptibility. In humans, Werners syndrome [50] is caused by variation in one of the DNA helicase genes [51]. Ageing is associated with altered gene expression; however, as yet, DNA studies have not identied any unexpected changes in old age [45, 47]. For completeness within this review, there are a number of, yet rare, inherited ageing conditions that are helpful in the understanding of the ageing process such as, though not excluding, Werners syndrome [50, 51], Hutchinson-Gilford Progeria syndrome [52 56] and Xeroderma pigmentosum [57]. Ageing and the skin The skin serves as a protective barrier between the bodys internal organs and the environment. Skin is a complex organ composed of many cell types and structures. It is divided into three key regions: epidermis, dermis and subcutaneous tissue. The epidermis, a cell-rich layer, is composed mainly of

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differentiating keratinocytes, which are the most numerous cell type of the skin, which ultimately form the skins external protective barrier to the environment. The epidermis also comprises pigment producing melanocytes and antigen presenting Langerhans cells. The basement membrane separates the epidermis from the dermis the dermis comprised primarily of extracellular matrix proteins, which are produced by broblasts. Vascular supply to the skin also resides in the dermis. Subcutaneous tissue consists of adipose (fat) cells, which support the connective tissue framework. Type I collagen is the most abundant protein of the skin connective tissue. This tissue also contains other types of collagen (III, V, VII), elastin, proteoglycans, bronectin and extracellular matrix proteins. Newly synthesized type I pro-collagen is secreted into the dermal extracellular space where it undergoes enzymatic processing, which results in the formation of collagen bundles responsible for the strength and resiliency of the skin. Skin ageing is inuenced by several factors including genetics, environmental exposure, hormonal changes and metabolic processes. Together these factors lead to cumulative alterations of skin structure, function and appearance [5869]. Skin failure and breakdown Notwithstanding, skin organ failure has been previously overlooked, as compared with other organs of the body, such as the heart, etc. Acute skin failure is a state of total dysfunction resulting from both different dermatological conditions as well as internal body responses [70]. It has been dened as loss of normal temperature control with an inability to maintain core body temperature and
Ageing UV exposure

failure to prevent percutaneous loss of uid, electrolytes and protein with a resulting imbalance and failure of the barrier to prevent penetration of foreign substances, infection, peripheral oedema and altered immune functioning [71]. Ageing skin is at risk of breakdown and ultimately failure. It has a thinner epidermis with attened dermal ridges making it less resistant to shearing forces. The complex biochemistry of the dermis is altered with age and the delicate balance between those enzymes that control remodelling and repair of the dermal matrix is also disrupted contributing to the overall loss of connective tissue and atrophy of the skin. Coupled with a reduced ability of the skin to regenerate and a less efcient protective immune functioning, it is not surprising that the skin of chronologically ageing individuals is at risk of breakdown and failure. Effects of ultraviolet light The inuence of the environment, notably solar UV irradiation, is of considerable importance for skin ageing [58, 60, 72, 73]. Historically, photoageing and chronological skin ageing have been considered distinct entities. Although the typical appearance of photo-aged and chronologically aged human skin can be readily distinguished, recent evidence indicates that chronologically aged and UV-irradiated skin share important molecular features including altered signal transduction pathways that promote matrix-metalloproteinase (MMP) expression, decreased pro-collagen synthesis and connective tissue damage (Fig. 1). Oxidative stress is thought to play a central role in initiating and driving the signalling events that lead to cellular response following UV irradiation.

Oxidative stress (ROS)

DNA mutations (changes to gene structure)

Signal transduction (changes to gene activity)

Protein alteration (structure and function)

Intracellular

& Homeostatic modifications

Extracellular

Figure 1 Role of oxidative stress in ageing and UV response: UV irradiation and ageing lead to increased ROS production, which alters gene and protein structure and function. This results in changes in intracellular and extracellular homoeostasis modifying cellular behaviour and cell-matrix interactions leading to impaired skin function [13, 14, 17, 73, 75].

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UV irradiation of skin increases hydrogen peroxides and other ROS and decreases anti-oxidant enzymes. These features are also observed in chronologically aged human skin. In both cases, increased ROS production alters gene and protein structure and function leading to skin damage. This suggests that UV irradiation accelerates many key aspects of the chronological ageing process in human skin. Based on this relationship between UV irradiation and chronological ageing, acute UV irradiation of human skin may serve as a useful model to study molecular mechanism of skin chronological ageing [57, 7276]. Effects of smoking Tobacco smoking in addition to seriously affecting the internal organs of the body, affects a persons appearance by altering the skin and body weight and shape. Skin damaged by smoke appears grey and wasted [77]. These changes increase the risk of more serious disorders and have a noticeable ageing effect on the body. Tobacco smoke released into the environment has a drying effect on the skins surface and it reduces the amount of blood ow to the skin thus depleting the skin of oxygen and essential nutrients [7781]. Squinting in response to the irritating nature of smoke and puckering of the mouth when drawing on a cigarette will cause wrinkles [8284]. Research has shown that the skin ageing effects of smoking may be because of increased production of collagenase [8590]. Collagen is the main structural protein of the skin which maintains skin elasticity. The more a person smokes, the greater the risk of premature wrinkling [82, 83]. Smokers in their 40s often have as many facial wrinkles as non-smokers in their 60s. In addition to facial wrinkling, smokers may develop hollow cheeks through repeated drawing on cigarettes; this is particularly noticeable in under-weight smokers resulting in a gaunt appearance. Smokers skin can be prematurely aged by between 10 and 20 years and although the damaging effects of cigarette smoke on the skin are irreversible, further deterioration can be avoided by cessation of smoking [81]. Effects of pollution Skin cancer is continually increasing, with most skin cancer deaths arising from melanoma [91, 92]. The most common skin cancers are basal cell carci 2008 proDERM GmbH. Journal compilation

noma (76%), squamous cell carcinoma (19%) and melanoma (5%). Skin cancers are most closely associated with, though not exclusively to ultraviolet B irradiation (UV-B) exposure, with most of a persons lifetime UV-B exposure occurring before the age of 18. Depletion of the earth ozone layer exacerbates serious genetic damage [93] and environmental pollution by combustion products of fossil fuels etc., is a major concern for all medical disciplines as it is predicted that the ozone layer will remain diminished for decades even after pollutants are replaced by non-ozone depleting substitutes [93]. Furthermore, UV-B is a strong immunosuppressive agent and therefore may have very signicant systemic effects related to the release of immunologically active molecules from the skin, such as tumour necrosis factor (TNF)-a and cis-urocanic acid, which themselves produce immunosuppressive effects including depression of delayed hypersensitivity, suppression of T-lymphocytes and activation of cutaneous herpes simplex infections [94, 95]. Despite its barrier properties, the skin is also a point of entry for substances capable of causing harm, e.g. exposure to xenobiotics, pesticides, topical drugs and cosmetics etc. Precise modelling of percutaneous exposure is needed to determine its importance in the absorption of many materials, as well as improved protective measures against exposure to hazardous chemicals [9698]. Signal cascades and skin damage The earliest detectable response of the skin cell to UV irradiation is the activation of multiple cytokine and growth factor cell surface receptors including epidermal growth factor receptor (EGF-R), TNF-a receptor, platelet activating factor (PAF) receptor, insulin receptor, interleukin (IL)-1 receptor and platelet derived growth factor (PDGF) receptor [75, 99, 100]. Activation of cell surface cytokine and growth factor receptors results in recruitment of adaptor proteins that mediate downstream signalling. Assembly of these signalling complexes causes the activation of l GTP-binding proteins, key upstream regulators of MAP kinases. The action of certain GTP-binding protein results in an increased formation of superoxide. This increased production of ROS participates in amplication of the signal leading to the activation of the downstream enzyme complexes [101]. ROS are necessary participants in multiple MAP kinase pathways [101103].

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The UV-induced increase of intracellular ceramide content may also contribute to activation of MAP kinase pathways. UV-induced ceramide generation appears dependent on increased ROS production as ceramide and ROS levels rise in together and that UV-induced ceramide production is inhibited by Vitamin E [104108]. MAP kinase activation results in the induction of transcription factor AP-1, which regulates the expression of many genes involved in the regulation of cellular growth and differentiation. AP-1 tightly regulates the transcription of several MMPs (matrix-metalloproteinase). MMPs which are upregulated by AP-1 include MMP-1 (interstitial collagenase or collagenase 1) initiates degradation of types I and III collagens; MMP-9 (gelatinase B), which further degrades collagen fragments generated by collagenases; and MMP-3 (stromelysin 1), which not only degrades basement membrane type IV collagen but also activates proMMP-1. UVinduced damage to skin connective tissue requires MMP induction. Collectively, MMP-1, MMP-3 and MMP-9 will completely degrade mature collagen in the skin and UV irradiation of human skin causes extracellular matrix degradation via induction of transcription factor AP-1 and subsequent increased MMP production [109111]. UV irradiation also impairs new type I collagen synthesis. Down-regulation of type I collagen is mediated, in part, by UV-induced AP-1, which negatively regulates transcription of COL1A1 and COL1A2 genes that encode for type I pro-collagen. The UV-induced down-regulation of collagen synthesis also occurs via mechanisms involving TGF-b and other cytokines. TGF-b, a major cytokine regulates multiple cellular functions notably differentiation, proliferation and induction synthesis of extracellular matrix protein synthesis. Moreover, TGF-b induces synthesis and secretion of the major extracellular matrix proteins, collagen and elastin. TGF-b also inhibits the expression of certain specic enzymes involved in the breakdown of collagen, including MMP-1 and MMP-3 [101, 112114]. Concluding remarks Oxidative stress is considered of primary importance in driving the ageing process. The original free radical theory of ageing purported that the molecular basis of ageing was derived from a lifetime accumulation of oxidative damage to cells

resulting from excess ROS produced as a consequence of aerobic metabolism. Although the skin possesses extremely efcient anti-oxidant activities, during ageing, ROS levels rise and anti-oxidant activities decline. The ROS are necessary in multiple MAP kinase pathways and the induction of AP-1, in turn, up-regulates expression of MMPs providing a plausible mechanism for the increased collagen degradation in aged human skin. Despite differences, there are many striking similarities in the molecular features of chronologically aged and UV-damaged skin. These similarities reect the pivotal role oxidative stress has in UVinduced skin responses and that the consequences of UV irradiation and ageing have a similar damaging impact on skin connective tissue. In part 2, we discuss clinical methods used in the assessment of skin ageing and the requirement for a disciplined approach to their use in such investigations. Acknowledgements The authors gratefully thank Professor Suresh Rattan, Department of Molecular Biology, University of Aarhus, Denmark, for his critical review and comment of the manuscript. This work was fully funded by proDERM. References
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