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Skin ageing and its treatment

Journal of Pathology
J Pathol 2007; 211: 241–251
Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/path.2098
Review Article
Skin ageing and its treatment
L Baumann*Department of Dermatology, University of Miami, Miami Beach, FL, USA Abstract
L Baumann, Department ofDermatology, University of The effects of chronic sun exposure on skin are readily apparent when skin not typically
exposed to the sun and skin regularly exposed to the sun are compared. While the sun is
not the only aetiological factor in the dynamic process of skin ageing, it is the primary
exogenous cause among several internal and environmental elements. Thus, photo-ageing,
the main focus of this article, is a subset of extrinsic skin ageing. The influence of the
sun in extrinsic skin ageing, as well as its role in potentially altering the normal course of

No conflicts of interest weredeclared. intrinsic (also known as natural or cellular) ageing, is discussed. Telomeres, the specialized
structures found at the ends of chromosomes, are believed to be integral to cellular ageing
as well as in the development of cancer. The ageing process, both intrinsic and extrinsic,
is also believed to be influenced by the formation of free radicals, also known as reactive
oxygen species. The loss of collagen is considered the characteristic histological finding in
aged skin. Wrinkling and pigmentary changes are directly associated with photo-ageing and
are considered its most salient cutaneous manifestations. Such photodamage represents the
cutaneous signs of premature ageing. In addition, deleterious consequences of chronic sun
exposure, specifically various forms of photo-induced skin cancer, are also linked to acute
and chronic sun exposure. The only known strategies aimed at preventing photo-ageing
include sun avoidance, using sunscreens to block or reduce skin exposure to UV radiation,
using retinoids to inhibit collagenase synthesis and to promote collagen production, and
using anti-oxidants, particularly in combination, to reduce and neutralize free radicals.
Copyright
2007 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.

Keywords:
photo-ageing; extrinsic ageing; intrinsic ageing; telomeres; free radicals;
collagen
Introduction
Cutaneous ageing
As implied above, there are two primary skin ageing The contribution or facilitating role of sunlight toward processes, intrinsic and extrinsic. Variations in individ- premature skin ageing has been discussed and debated ual genetic background are thought to govern intrinsic by dermatologists since the end of the 1800s [1], ageing, which results as time passes. By definition, but convincing the public regarding the risks of sun this form of ageing is inevitable and, thus, apparently exposure remains an uphill battle, despite success in not subject to manipulation through changes in human the use of the skin protection factor (SPF) system behaviour. Conversely, extrinsic ageing is engendered in topical products. Still, an inordinate number of by factors originating externally that are introduced patients visiting dermatologists complain about, and to the human body, such as smoking, excessive alco- seek treatment for, the most salient manifestations of hol consumption, poor nutrition, and chronic exposure solar exposure — wrinkling and unwanted pigmenta- to the sun. Exposure to such elements, which falls tion, the tell-tale symptoms of photo-ageing.
within the voluntary realm, although it may sometimes While the sun is not the only aetiological factor occur under duress, is not inevitable and thus repre- in skin ageing, it is the primary exogenous cause sents premature skin ageing. Of these external factors, among several internal and environmental elements.
sun exposure is considered to be far and away the This chapter will focus chiefly on photo-ageing, or the most significantly deleterious to the skin. Indeed, 80% extrinsic skin ageing due to the influence of the sun, of facial ageing is believed to be due to chronic sun but also on the role of the sun in potentially altering the normal course of intrinsic, or natural, ageing. In Skin that ages intrinsically is smooth and unblem- addition, how both kinds of ageing affect the skin will ished, and characterized by normal geometric pat- be discussed, along with strategies aimed at preventing terns, with some exaggerated expression lines. His- tologically, such skin manifests epidermal and dermal Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
www.pathsoc.org.uk L. Baumann
atrophy, flattening of the epidermal rete ridges, as well shortening and somatic tissue ageing. It is impor- as reduced numbers of fibroblasts and mast cells [3,4].
tant to note that the epidermis is one of the few In addition, increases are seen in the number of col- regenerative tissues to express telomerase [13]. Fur- lagen fibrils as well as the ratio of collagen III to ther, in a recent investigation of progressive telomere shortening, in 52 specimens of normal human epi- Exposed areas of the skin, typically the face, chest dermis and 48 specimens of lingual epithelium col- and extensor surfaces of the arms, display the major- lected at autopsy from subjects who died between 0 ity of extrinsically aged skin, which results from the and 101 years of age, researchers determined that the cumulative effects of life-long ultraviolet radiation telomere shortening associated with ageing is charac- (UVR) exposure. Rhytides, pigmented lesions (such as terized by tissue-specific loss rates [14]. Indeed, the ephelides, lentigines, and patchy hyperpigmentation) natural, progressive shortening of telomeres may be and depigmented lesions (eg guttate hypomelanosis) one of the primary mechanisms of cellular ageing in comprise the clinical presentation of photo-aged skin.
skin [15]. Telomeres and other cellular constituents Losses in tone and elasticity are also observed in also sustain low-grade oxidative damage as a result photo-aged skin, along with increased skin fragility, of aerobic cellular metabolism, which contributes to areas of purpura due to blood vessel weakness, and intrinsic ageing [16]. Currently, there are no avail- benign lesions (eg acrochordons, keratoses, and telang- able topical skin care products, systemic drugs or other iectases). On the Glogau Photo-ageing Scale, which treatment options that target telomerase because cur- classifies the extent of clinical photodamage, patients rent data do not adequately demonstrate that extending with a significant history of sun exposure would likely telomere length can be safely performed. One argu- receive a score that is higher than expected for their ment for eventual telomerase-based therapies is the age, just as patients with a history of minimal sun belief that inhibiting telomerase may also have anti- exposure would likely score lower than expected for proliferative and apoptosis-inducing effects not related to the role this ribonucleoprotein plays in shortening The histopathological identification of photo-aged telomeres during cell division [17].
skin is made easily, as it is characterized by elastosis.
Werner syndrome (WS) is an autosomal recessive Epidermal atrophy and distinct alterations in collagen disorder in which the causative gene, WRN, encodes and elastic fibres are also associated with photo- a member of the RecQ-like subfamily of DNA heli- aged skin. In particular, skin that is marked by cases [18]. The Werner protein (Wrn), a multifunc- extreme or severe photo-ageing exhibits fragmented, tional nuclear protein exhibiting 3 –5 exonuclease and thickened and more soluble collagen fibres [6]. Elastic ATP-dependent helicase activities, is known to play fibres also experience fragmentation and may exhibit a role in numerous DNA metabolic pathways and to progressive cross-linkage and calcification [7]. Such be available in WS patients at reduced levels [19].
marked deterioration in the condition of collagen and Patients with WS exhibit signs of accelerated age- elastic fibres has been demonstrated to progress with ing and the premature onset of various age-related continued exposure to UV radiation. Overall, ageing disorders; among these, the incidence of sarcomas skin is marked by increased inelasticity, fragmentation and other tumours of mesenchymal origin is higher than in the population at large [20]. In one study,mouse embryo fibroblasts derived from homozygous WS embryos exhibited premature loss of prolifera-tive capacity [21]. In a more recent mouse model Telomeres, the specialized structures found at the ends study, investigators found that exhaustion of telomere of eukaryotic chromosomes, have come under increas- reserves elicited WS and telomere dysfunction pro- ing scrutiny and are now believed to play an essen- voked various Werner-like symptoms, including hair tial role in the intrinsic ageing process at a cellu- greying, alopecia, cataracts, osteoporosis, type II dia- lar level. Intact telomeres are integral in extending betes and premature death [22]. In addition, accel- the lifespan of cells [9]. With age, telomere length erated replicative senescence, chromosomal instabil- shortens. This telomeric erosion has come to be seen ity, especially non-epithelial tumours often associated as a gauge by which to measure ageing, a verita- with WS, were exhibited in this model, with telom- ble internal ageing clock, and the basis for one of ere shortening implicated as the primary cause. Given the presently favoured theories on ageing [10]. One the association of WS and telomere shortening and the implication of this theory places ageing and cancer roles of telomeres and telomerase in cellular ageing, on opposite sides of the same coin. That is, telom- further research into these interconnected phenomena erase, the cellular reverse transcriptase enzyme that will likely have an impact on further elucidating our stabilizes or lengthens telomeres, is expressed in about understanding of the ageing process, as well as poten- 85–90% of all human tumours but absent in many somatic tissues [11,12]. Consequently, most cancercells, unlike healthy ones, are not programmed forapoptosis, or cell death. In other words, the pres- ence of telomerase is associated with telomere sta- Extrinsic ageing is largely preventable, by nature and bility and tumourigenesis, its absence with telomere by definition. Factors with clearly exogenous origins, J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Skin ageing and its treatment
including smoking, poor nutrition and especially solar skin as it ages occur throughout the epidermis, dermis exposure, are the main causes of extrinsic, premature, and subcutaneous tissue and can manifest in discrete cutaneous ageing. Moreover, sun exposure, as stated and broad alterations in skin topography.
previously, is believed to account for 80% of facialageing [23]. Skin damage results from ultraviolet exposure through several mechanisms, including theformation of sunburn cells as well as thymine and When considering the visually obvious nature of skin, pyrimidine dimers, collagenase production, and the it seems counter-intuitive to suggest that the age- induction of an inflammatory response. Sunburn cells, related changes in the dermis are more pronounced or UV-induced apoptotic cells, have long been used than those in the epidermis, but this is nonetheless as markers by which to evaluate skin damage caused the case. That said, the epidermis does manifest some by sun exposure. UV-induced apoptosis is mediated important changes related to ageing. While some stud- by caspase-3, high levels of which are thought to be ies indicate that aged skin is characterized by a thinner good indicators of the presence of cellular apoptosis epidermis [32], other studies do not point to such a [24]. Activation of apoptosis occurs in a pathway that finding [33]. There is general agreement, however, that involves caspase-7 [25]. Mast cells and macrophages the thickness of the stratum corneum does not change are found in greater numbers in photo-aged skin with age. In a study comparing the effects of intrin- and are also thought to be involved in its causative sic and extrinsic ageing, histopathological examination of 83 biopsies from sun-exposed and protrected skin Signalling through p53 after telomere disruption is in healthy volunteers aged 6–84 years revealed epi- also linked to ageing in addition to photodamage, in dermal thickness to be constant across the decades in association with UVB more so than UVA [27,28].
both sun-exposed and -protected skin, with the thick- Histological examination has demonstrated that more ness found to be greater in sun-exposed skin [34].
infiltrating mononuclear cells are found in skin chron- In a different study, the spinous layer of a wrinkle ically exposed to the sun in comparison to protected was shown to be thinner at the base than at the flanks skin [29]. While much more remains to be understood [35]; in addition, according to this study, fewer kera- regarding the mechanisms through which a cascade of tohyaline granules are present in the wrinkle base as adverse health effects are induced by UV exposure, it is well known that photo-ageing, photocarcinogene- In aged skin, the intersection of the epidermis sis and photo-immunosuppression are sequelae of UV and dermis, known as the dermal –epidermal junction exposure, particularly the UVA range (320–400 nm) (DEJ), is known to be altered, ie aged epidermis manifests a flattened DEJ with a correspondingly Interestingly, telomeres do not appear to play a diminished connecting surface area. In a study of central role in extrinsic ageing. In a recent study, in abdominal skin, DEJ surface area was shown to be which telomere length was measured in 76 specimens reduced from 2.64 mm2 in subjects aged 21–40 years of epidermis from sun-protected sites, 24 specimens of to 1.90 mm2 in subjects aged 61–80 [36]. It is thought epidermis from sun-exposed sites and 60 specimens that such a loss of DEJ surface area may contribute to of dermis, comparisons showed telomere length to the increased fragility of the skin associated with age be shorter in the epidermis. Intrinsic senescence was and may also lead to reduced nutrient transfer between evidenced by reduction in telomere length in the epidermis and dermis with age. Telomere shorteningwas not associated with photo-ageing in this study, Decreased cell turnover
as telomere length was not shown to be significantlydifferent between sun-exposed and sun-protected sites Other important age-related changes occur in the epidermal layer. Between the third and eighth decades Currently, sun avoidance and the use of sunscreens of life, the epidermal turnover rate slows from 30% to are the only defence against sunburn cell formation; 50% [37]. Stratum corneum transit time was shown by they can also protect against thymine dimer forma- Kligman to be 20 days in young adults and 30 or more tion. Theoretically, the fewer sunburn cells present, days in older adults [38]. Such a cell cycle lengthening the lower the skin damage level due to UV expo- in older adults coincides with a protracted stratum corneum replacement rate, epidermal atrophy, slowerwound healing and often less effective desquamation.
Indeed, older patients have been demonstrated to Characteristics of ageing skin
require double the time to re-epithelialize followingdermabrasion resurfacing procedures in comparison to The key difference between intrinsic and extrinsic younger patients [39]. The cascade of changes related ageing is that the latter falls within the volitional to decelerated cell turnover results, in older skin, in the control of the individual. Nevertheless, there are development of heaps of corneocytes that render the salient features exhibited by aged skin, regardless of skin surface rough and dull in appearance. In response the cause(s) of skin ageing. The changes undergone by to these phenomena, many cosmetic dermatologists J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
L. Baumann
use products (eg hydroxy acids, retinoids) to accelerate ratio of Type III to Type I collagen has been shown to the cell cycle, in the belief that a faster turnover rate increase, due, significantly, to an appreciable loss of will yield improvements in skin appearance and speed collagen I [48]. In addition, the overall collagen con- wound healing following cosmetic procedures.
tent per unit area of skin surface is known to declineapproximately 1%/year [49]. In irradiated skin, colla- gen I levels have been shown to be reduced by 59%[50]; this reduction was found to be linked to the extent Approximately 20% of dermal thickness disappears as of photodamage [51]. Although collagen I is the most people become elderly [40]. Aged dermis has been abundant and significant collagen type found in the shown through structural examination to be relatively skin, the effects of ageing are seen in other types of acellular and avascular [41]. Changes in collagen production and the development of fragmented elastic An integral constituent of the DEJ, collagen IV fibres also characterize normal aged dermis. Dermis imparts a structural framework for other molecules and that is also photo-aged exhibits disorganized collagen plays a key role in maintaining mechanical stability.
fibrils and the accumulation of abnormal elastin- No significant differences have been found in collagen containing material [42,43]. As the three primary IV levels in sun-exposed skin compared to unexposed structural components of the dermis, collagen, elastin skin, but significantly lower levels of collagen IV have and glycosaminoglycans have been the subjects of the been identified at the base of wrinkles in comparison majority of anti-ageing research pertaining to the skin.
to the flanks of the same wrinkles. The mechanicalstability of the DEJ may be adversely affected by thisloss of collagen IV, thereby contributing to wrinkle Collagen
The primary structural component of the dermis and Collagen VII is the primary constituent in anchoring the most abundant protein found in humans, collagen fibrils that attach the basement membrane zone to is responsible for conferring strength and support to the underlying papillary dermis. In one study, a human skin. Over time, the structural proteins and significantly lower number of anchoring fibrils were main components of the skin deteriorate, resulting in identified in patients with chronically sun-exposed skin the cutaneous signs of ageing. Intrinsically aged skin is in comparison to normal controls. It was theorized by characterized by epidermal and dermal atrophy as well the researchers that wrinkles may form as a result of as flattening of the rete ridges [44]. Knowledge of the a weakened bond between the dermis and epidermis, role of collagen in the ageing process over 30 years due to anchoring fibril degradation [53]. A more recent ago helped to establish the use of bovine collagen as a study showed such a loss of collagen VII to be more filling agent to temporarily replace collagen lost with marked in the base of the wrinkle (as seen with age in soft tissue augmentation procedures. Injectable collagen IV in the same study) [54].
human-derived products, such as Zyderm and Zyplast, In the last 15 years, the pathogenesis of UVR- have also emerged during the last decade for these induced collagen damage has been well understood purposes. Other products that contain ingredients such and characterized. For instance, it is known that UVR as vitamin C and glycolic acid, and labelled as ‘anti- exposure significantly up-regulates the synthesis of wrinkle creams’, are promoted in some cases for several types of collagen-degrading enzymes known their claimed capacity to enhance collagen synthesis.
as matrix metalloproteinases (MMPs). First, UV expo- Such products are not harmful, but cannot yet truly sure leads to an increase in the amount of the transcrip- match the desired effects. In fact, little is known tion factor c-jun; c-fos, the other transcription factor even about the pathogenesis of wrinkles [45]. The involved in this mechanistic chain, is already abun- fact that neither an animal nor an in vitro model of dant without UV exposure. Activator protein-1 (AP-1) wrinkling has yet been established may help to explain is then formed by the combination of c-jun and c- this gap in knowledge. It is well known, however, fos. In turn, AP-1 activates the MMP genes, which that alterations in collagen play an integral role in stimulate the production of collagenase, gelatinase and the ageing process. This, in turn, partly explains the stromelysin. Collagen degradation is mediated by AP- popularity of collagen-containing products intended 1 activation and by inhibition of transforming growth factor (TGF)β signalling [55]. Research in humans has Of the dry skin mass, 70% is comprised of colla- shown that within hours of UVB exposure, MMPs, gen [46]. In aged skin, collagen is characterized by specifically collagenase and gelatinase, are produced thickened fibrils, organized in rope-like bundles, that [56]. Multiple exposures to UVB engender a sus- appear to be in disarray in comparison to the pattern tained induction of MMPs [57]. Given that collagenase observed in younger skin [47]. In addition, lower lev- attacks and degrades collagen, long-term elevations in els of collagen are synthesized, in vivo and in vitro, the levels of collagenase and other MMPs likely yield by aged fibroblasts. The ratio of collagen types found the disorganized and clumped collagen identified in in human skin also changes with age. In young skin, photo-aged skin. Notably, these MMPs may repre- collagen I comprises 80% and collagen III comprises sent the mechanism through which collagen I levels about 15% of total skin collagen; in older skin, the decline in response to UV exposure. By characterizing J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Skin ageing and its treatment
the wide-ranging effects of UV in activating cell sur- acid (HA), dermatan sulphate (both of which are two face growth factor and cytokine receptors, researchers of the most prevalent GAGs) and chondroitin sulphate.
have been able to ascertain that skin ageing (extrin- These compounds render normal skin plump, soft and sic and intrinsic) is marked by elevated AP-1 activity hydrated, and are believed to assist in maintaining and MMP expression, inhibited TGFβ signalling, as proper salt and water balance. Several studies sug- well as reduced collagen synthesis and greater colla- gest that GAGs, particularly HA, have been found to gen degradation [58]. These changes are likely to be be reduced in amount in photo-aged skin [67]. Some studies offer conflicting reports, however, suggestingno changes in the level of GAGs in aged skin [68].
The fact that HA is synthesized in the epidermis aswell as the dermis likely accounts for this discrepancy Alterations in elastic fibres are so strongly associated in findings. In skin that ages intrinsically, the total HA with photo-aged skin that ‘elastosis’, an accumulation level in the dermis remains stable; however, epidermal of amorphous elastin material, is considered pathog- HA diminishes almost completely [69].
nomonic of photo-aged skin. Indeed, UV exposureinduces a thickening and coiling of elastic fibres inthe papillary dermis. These changes also occur in the Hyaluronic acid
reticular dermis as a result of chronic UV exposure Photoaged skin has been shown to be characterized [59]. Examination by electron microscopy of elastic by reduced levels of hyaluronic acid (HA) and ele- fibres in UV-exposed skin has revealed a reduction in vated levels of chondroitin sulphate proteoglycans the number of microfibrils and increases in interfibril- [70]. Such patterns, intriguingly, are also observed lar areas, the complexity of the shape and arrangement in scars. HA is found in young skin at the periph- of the fibres and the number of electron-dense inclu- ery of collagen and elastin fibres and where these sions [60]. In addition, small amounts of sugar and types of fibres intersect. In aged skin, such connec- lipids and an abnormally high level of polar amino tions with HA disappear [71]. It is possible that the acids have been found in elastin extracted from the decreases in HA levels, which contribute to its disas- skin of elderly patients [61]. The underlying aetiology sociation with collagen and elastin as well as reduced of age-related changes in elastin is not as well under- water binding, may be involved in the changes noted stood as such changes in collagen; however, matrix in aged skin, including wrinkling, altered elasticity, metalloproteinases are thought to play a role because reduced turgidity and diminished capacity to support MMP-2 has been demonstrated to degrade elastin [62].
The initial response of elastic fibres to photodam- As one of the primary GAGs, HA can bind 1000 age is understood, however, to be hyperplastic, result- times its weight in water, and may help the skin ing in a greater amount of elastic tissue. The level retain and maintain water. It is found in all connective of sun exposure determines the magnitude of the tissue and is produced mainly by fibroblasts and hyperplastic response. In aged elastic fibres, a sec- keratinocytes in the skin [72]. HA is localized not only ondary response to photodamage occurs but is degen- in the dermis but also in the epidermal intercellular erative, with decreases observed in skin elasticity and spaces, especially the middle spinous layer, but not resiliency [63,64]. Older skin that has experienced this in the stratum corneum (SC) or stratum granulosum degenerative reaction is characterized by changes in [73]. Aged skin, which is less plump than youthful the normal pattern of immature elastic fibres, called skin, is characterized by decreased levels of HA. The oxytalan, that are located in the papillary dermis.
role of HA in skin hydration is not clear and HA These fibres form a network in young skin that ascends does not penetrate the skin upon topical application perpendicularly from the uppermost section of the pap- [74]; however, this has not stopped many companies illary dermis to just beneath the basement membrane.
from putting HA in topical skin care products and This network gradually disappears with age, however claiming efficacy. HA is used successfully, however, [65]. Consequently, skin elasticity is also gradually as a temporary dermal filling agent in soft tissue lost with age [66]. The phenomenon of sagging skin often observed in the elderly may, in fact, be due inlarge part to this loss of elasticity.
Melanocytes
With age, there is a reduction in the number of Glycosaminoglycans (GAGs)
melanocytes in the range 8–20%/decade. Clinically, GAGs, along with collagen and elastin, are among the this decrease is observed as a reduction in the number primary constituents of dermal skin and are responsi- of melanocytic nevi in older patients [75]. The skin ble for conferring the outward appearance of the skin.
of older patients is less able to protect itself from the These polysaccharide chains, with repeating disaccha- sun because melanin, which is reduced in the elderly, ride units attached to a core protein, are also important absorbs carcinogenic UV radiation. Therefore, older molecules because they exhibit the capacity to bind people are more susceptible to developing sun-induced water up to 1000 times their volume. There are numer- cancers. For this reason, sun protection remains impor- ous members in the GAG family, including hyaluronic tant even for elderly patients, despite the fact that J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
L. Baumann
the majority of an individual’s harmful sun exposure in low-humidity environments. In addition to dryness, occurs during the first two decades of life. It is not aged skin is often characterized by roughness, wrin- ‘too late’ for healthy elderly people to begin adding a kling, skin pallor, hyper- or hypopigmentations, laxity, sunscreen to their skin care regimens.
fragility, easy bruising and benign neoplasms.
Aged skin has been shown through numerous stud- With age, the appearance and surface texture of skin ies to be relatively avascular. In one study a 35% can change dramatically, as represented by the devel- reduction in the venous cross-sectional area in aged opment of acrochordons (skin tags), cherry angiomas, skin was demonstrated in comparison to young skin seborrheic keratoses, lentigos (sun spots) and seba- [76]. Such a loss in the vascular network is especially ceous hyperplasias, among other lesions and cuta- noticeable in the papillary dermis, with the disappear- neous alterations. Patients of dermatologists and plas- ance of the vertical capillary loops. Reduced blood tic surgeons often request removal of these benign flow, depleted nutrient exchange, inhibited thermoreg- neoplasms. Various destructive treatment modalities ulation, decreased skin surface temperature and skin are available, including hyfrecation and sundry laser pallor are associated with the reduction of vascularity.
Treatment
Site-specific changes, including gains and losses, areknown to occur in subcutaneous tissues that also Photoaged skin is treated with various in-office pro- influence the appearance of the elderly and their skin.
cedures and numerous topical agents, most of which Subcutaneous fat diminishes in the face, dorsal aspects are intended to ‘resurface’ the epidermis. Essentially, of the hands and the shins. Fat amasses with ageing, this translates to removing the damaged epidermis though, in other regions, particularly the waist in and, in some cases, dermis, and replacing the tissue with remodelled skin layers. Several anti-oxidants areincorporated into topical skin care products, including The role of free radicals in photo-ageing vitamins C and E, co-enzyme Q10, ferulic acid, greentea, idebenone, pycnogenol and silymarin. Resurfac- The ageing process is believed to be at least partially ing procedures have been shown to sometimes spur due to the formation and activity of free radicals, also the formation of new collagen with a normal staining known as reactive oxygen species (ROS). Free radicals pattern, as opposed to the basophilic elastotic masses are composed of oxygen molecules with an unpaired of collagen characteristic of photo-aged skin [81]. It is electron and are engendered by several exogenous and possible that the potential of growth factors, cytokines endogenous factors, including UV exposure, pollution, and telomerase will eventually be harnessed via tech- stress, smoking and normal metabolic processes. Fur- nological advancement and innovation in the burgeon- ther, some evidence suggests that free radicals induce ing fields of tissue engineering and gene therapy [82].
alterations in gene expression pathways, which in turn Although there are several treatments available for contribute to the degradation of collagen and the accu- aged skin, prevention of extrinsic ageing remains mulation of elastin emblematic of photo-aged skin the best approach and should be encouraged to all [78]. Anti-oxidants neutralize free radicals by supply- patients. Of course, this entails avoiding exposure ing another electron, delivering an electron pair to an to the sun, using sunscreen when sun avoidance is oxygen molecule and stabilizing it in the process.
impossible, avoiding cigarette smoke and pollution,eating a diet high in fruits and vegetables, and takingoral anti-oxidant supplements or topical anti-oxidant Changes in skin appearance
formulations. The regular use of prescription retinoidscan also help prevent or treat wrinkles.
Dry, scaly skin is frequently seen in the elderly.
The degradation or loss of skin barrier function with Prevention
increasing age is partly accountable for this manifes-tation. The recovery of damaged barrier function has The formation of rhytides is considered the most been demonstrated to be slower in aged skin, resulting conspicuous and common manifestation, and nearly a in greater susceptibility to developing dryness. This sine qua non feature, of skin ageing. Wrinkles appear is a multifactorial process due, in part, to lower lipid as a result of changes in the lower, dermal layers of the levels in lamellar bodies [79] and a decrease in epi- skin. It might come as a surprise to many consumers, dermal filaggrin [80]. Increased trans-epidermal water given the ubiquity of advertising that touts the newest loss (TEWL) is also exhibited by aged skin, leaving topical formulations to eliminate wrinkles and the the stratum corneum more susceptible to becoming dry related expenditure of millions of dollars by consumers J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Skin ageing and its treatment
on these ‘anti-ageing’ products, that few skin care greater clarity and certainty, however. For example, product ingredients have the capacity to penetrate far free radical activation of the MAP kinase pathways enough into the dermis to ameliorate deep wrinkles.
has been shown to stimulate collagenase production, Prevention of wrinkle development, therefore, has which leads to the breakdown of collagen [93]. Specif- assumed a fundamental status in anti-ageing skin care ically, Kang et al showed that pretreating human skin [83]. To prevent the formation of wrinkles, it is with the anti-oxidants genistein and N-acetyl cysteine necessary to halt the degradation of the skin’s three inhibited the UV induction of the cJun-driven enzyme primary structural constituents, collagen, elastin and collagenase. The use of anti-oxidants to hinder these HA, since all three components are known to decline pathways is thought to inhibit photo-ageing by pre- with age. Consequently, most anti-ageing procedures venting collagenase production and its resulting detri- and products are designed or formulated with the mental influence on collagen. Interestingly, this study intention of salvaging at least one of these basic showed that, although genistein and N-acetyl cys- cutaneous substances. Because the technology required teine exhibit anti-oxidant activity, these anti-oxidants to suitably deliver these compounds into the skin has exerted no effect on UV-induced erythema. Previous not yet been developed, topical products containing work has also pointed to the likelihood that using collagen, elastin or HA are unable to serve as adequate anti-oxidants in combination confers synergistic ben- replacements for what is lost from the skin through efits. In a randomized, double-blind, parallel-group, ageing. Although no products replenish these key skin placebo-controlled study of the effects of an oral com- components, some products do promote the natural bination of vitamins C and E, carotenoids, selenium synthesis of these substances. For example, collagen and proanthocyanidins, participants who took the anti- production has been shown to be stimulated by the use oxidant combination before exposure to UVB exhib- of retinoids [84], vitamin C [85] and copper peptide.
ited a difference in MMP-1 production in compar- Collagen synthesis may also be brought about through ison to the placebo group (p < 0.05) [94]. Similar the use of oral vitamin C [86]. In animal models, to the study by Kang, there were no significant dif- retinoids have been shown to increase production of ferences between the oral anti-oxidant group and the HA [87] and elastin [88]. HA levels are also thought to placebo group regarding minimal erythema dose of the be augmented with glucosamine supplementation [89].
There are no products yet approved for increasing the In yet another recent study of the effects of com- production of, or enhancing, elastin.
bined anti-oxidants, one group of subjects was treated Because inflammation is a known contributor to daily with a base cream containing 0.05% ubiquinone the degradation of collagen, elastin and HA, reducing (co-enzyme Q10), 0.1% vitamin E and 1% squa- inflammation is another integral approach to prevent- lene, and 50 mg co-enzyme Q10, 50 mg D-RRR-α- ing wrinkle formation. Anti-oxidants, all of which dis- tocopheryl acetate and 50 µg selenium were orally play various distinguishing characteristics and activ- administered, while the second group was treated ities, are believed to be an important focus in this with base cream only [95]. Patients treated with endeavour, as these free radical scavengers protect the topical anti-oxidant cream alone exhibited sig- the skin via several mechanisms that are just begin- nificant increases in the concentration of co-enzyme ning to be elucidated. Skin inflammation is a known Q10, D-RRR-α-tocopherol and squalene in the sebum sequela of free radicals directly acting on cytokine (although not in the stratum corneum or plasma). The and growth factor receptors in dermal cells and ker- group treated both topically and orally also demon- atinocytes. Cytokines and growth factors are known to strated higher levels of vitamin E and co-enzyme Q10 play a role in skin ageing, but the exact nature of their significance has not yet been clarified. Presently, these In terms of preventing the effects of photo-ageing, compounds are understood to function synergistically it is not yet known which anti-oxidants are the most in a complex cascade of events requiring the inclusion effective. Using topical and oral anti-oxidants in com- of several types of cytokines and growth factors [90].
bination will likely be the favoured recommendation The process is thought to be induced by UV expo- in the near future. Anti-oxidants should also be used in sure, which affects growth factor and cytokine recep- combination with sunscreens and retinoids to enhance tors in keratinocytes and dermal cells, contributing to their protective effects. Indeed, it is worth remem- downstream signal transduction by spurring mitogen- bering that not all sunscreens have an anti-oxidant activated protein (MAP) kinase pathways (specifi- effect and not all anti-oxidants have a sunscreen effect.
cally, extracellular signal-regulated kinase, c-jun N- However, a recent Duke University study has demon- terminal protein kinase, and p38), which collect in strated that vitamins C and E combined with ferulic cell nuclei and form cFos–cJun complexes of tran- acid impart both a sunscreen effect and an anti-oxidant scription factor AP-1 and trigger the MMPs col- lagenase, 92 kDa gelatinase and stromelysin, whichattack collagen and other connective tissue of the skin The direct effects of free radicals on the ageing Conceivably, volumes could be written on the plethora process and cutaneous ageing are understood with of natural compounds found in recent years to exhibit J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
L. Baumann
anti-oxidant activity. That is to say, an exhaustive with pycnogenol appeared to ease the effects of survey of green tea, tea tree oil, grape seed extract, UV radiation on the skin, specifically reducing ery- vitamins C and E, ferulic acid, etc. would far exceed thema, in 21 volunteers [106]. The UV radiation the limits of this chapter. A few of the anti-oxidant level necessary to reach one minimal erythema dose ingredients that have recently gained favour and atten- (MED) was significantly elevated during supplemen- tation. In addition to its anti-oxidant activity, pyc- Coenzyme Q10 or ubiquinone is a fat-soluble anti- nogenol is known to impart anti-inflammatory effects, oxidant found in all cells as part of the electron which are believed to result, at least in part, from transportation chain responsible for energy production, its inhibition of IFNγ -induced expression of ICAM-1 and has been shown to exhibit antiapoptotic activity [97]. It also naturally occurs in fish, shellfish, spinach Of course, sun avoidance and sunscreen use are and nuts. Like the key constituents of the skin, co- well established to be the primary components in enzyme Q10 has been shown to diminish with age in anti-ageing regimens, although still underappreciated animals and humans [98]. While UV light is known to by many segments of the public. A recent study remove vitamins C and E, glutathione and co-enzyme in the Journal of the American Medical Association Q10 from the epidermal and dermal layers of the skin, specifically reinforces the utility of sunscreen; in co-enzyme Q10 is consistently the first anti-oxidant to this study, children with the proclivity to freckle developed 30–40% fewer freckles when daily treated Derived from tropical fern, Polypodium leucoto- with an SPF 30 sunscreen, as compared to children not mos (PL) extract has exhibited potent anti-oxidant treated with a sunscreen [108]. This study buttresses activity. The incidence of phototoxicity was demon- dermatologists’ recommendations for sun protection strated to decrease after oral PL administration in in preventing the development of these pigmented subjects receiving psoralen–UVA (PUVA) treatment lesions, which not only make the skin appear older [99], as well as in normal healthy subjects [100].
but are associated with an increased risk of melanoma.
In another study, PL-treated keratinocytes and fibro- Clearly, sun avoidance is not easy to manage and is blasts exposed to UV displayed significantly amelio- often impossible, as well as being an unpopular or rated membrane integrity, mitigated lipid peroxida- poorly received suggestion among many patients. That tion, increased elastin expression and inhibited MMP- said, practitioners should gauge the receptivity of their patients and recommend as stringent a sun-avoidance Silymarin, a naturally occurring polyphenolic flavo- regimen as will likely be accepted. At the very least, noid or flavonolignans compound derived from the patients should be discouraged from any exposure to seeds of the milk thistle plant Silybum marianu, tanning beds or engaging in unnecessary sun exposure, has been shown in several animal studies to exhibit particularly between 10 a.m. and 4 p.m. Using a anti-oxidant, anti-inflammatory and immunomodula- Wood’s light to show patients the sun damage that tory properties that may contribute to preventing skin they have already incurred can be a useful approach cancer as well as photo-ageing [102]. The beneficial toward persuading them to curb their sun exposure and influence of silymarin is primarily ascribed to sily- strive for feasible sun avoidance. This demonstration bin, which has been demonstrated to be bioavailable can also convince patients to incorporate protective in skin and other tissues after systemic administra- measures, such as use of sunscreens, anti-oxidants and tion [103]. In addition, topical application of silybin retinoids, particularly since many patients mistakenly before or directly after UV exposure has been found believe, before being convinced otherwise, that their to confer potent protection against UV-induced epi- sun exposure is minimal and that any behavioural dermal damage, by depleting thymine dimer-positive modification is unwarranted. Indeed, sunscreen should be recommended for daily use, even when the patient Pycnogenol, a plant-derived substance found in intends to remain indoors. Along these lines, patients many plant extracts, such as pine bark, grapes and should be reminded that UVA rays have the capacity apples, is rich in the potent free radical-scavenging to penetrate glass, so they should also limit their group of compounds known as procyanidins (also risk at home and at work by not lingering near sun- called proanthocyanidins). Procyanidins are also con- splashed windows. UVA shields placed on windows tained in several other plants or parts thereof known can provide some protection, however. Finally, sun- for conferring anti-oxidant activity, including grape protective clothing, such as a broad-brimmed hat and seed, grape skin, bilberry, cranberry, blackcurrant, SPF 45 clothing, should be encouraged for patients green tea, black tea, blueberry, blackberry, straw- as general advice for when sun avoidance is not berry, black cherry, red wine and red cabbage. In practical and for those who anticipate prolonged one study, Skh : hr hairless mice pretreated with pyc- nogenol concentrations of 0.05–0.2% demonstrated adose-dependent reduction of the inflammatory sun- Conclusion
burn reaction (oedema) following minimally inflam-matory daily exposures to solar-simulated UV radi- Skin ageing is a dynamic, multifactorial process, ation [105]. In another study, oral supplementation best characterized and understood in dichotomous J Pathol 2007; 211: 241–251 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Skin ageing and its treatment
expressions: intrinsic or natural ageing is cellularly 8. Roupe G. Skin of the aging human being. Lakartidningen determined as a function of heredity, is inevitable 2001;98(10):1091–1095.
and results in cutaneous alterations; extrinsic ageing, 9. Geserick C, Blasco MA. Novel roles for telomerase in aging.
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which also manifests in cutaneous changes, originates 10. Boukamp P. Ageing mechanisms: the role of telomere loss. Clin from exogenous sources and is avoidable. In other Exp Dermatol 2001;26(7):562–565.
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synonymous with, although technically a subset of, 13. Boukamp P. Skin aging: a role for telomerase and telomere dynamics? Curr Mol Med. 2005;5(2):171–177.
The American Academy of Dermatology, practising 14. Nakamura K, Izumiyama-Shimomura N, Sawabe M, Arai T, Aoyagi Y, Fujiwara M, et al. Comparative analysis of telomere dermatologists and other clinicians have been preach- lengths and erosion with age in human epidermis and lingual ing the mantra that ‘there is no such thing as a healthy epithelium. J Invest Dermatol 2002;119(5):1014–1019.
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