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Keywords:

  • ageing skin;
  • genital skin;
  • skin pigmentation;
  • photodamage;
  • UV exposure

Synopsis

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

As the proportion of the ageing population in industrialized countries continues to increase, the dermatological concerns of the aged grow in medical importance. Intrinsic structural changes occur as a natural consequence of ageing and are genetically determined. The rate of ageing is significantly different among different populations, as well as among different anatomical sites even within a single individual. The intrinsic rate of skin ageing in any individual can also be dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light. Photodamage, which considerably accelerates the visible ageing of skin, also greatly increases the risk of cutaneous neoplasms. As the population ages, dermatological focus must shift from ameliorating the cosmetic consequences of skin ageing to decreasing the genuine morbidity associated with problems of the ageing skin. A better understanding of both the intrinsic and extrinsic influences on the ageing of the skin, as well as distinguishing the retractable aspects of cutaneous ageing (primarily hormonal and lifestyle influences) from the irretractable (primarily intrinsic ageing), is crucial to this endeavour.

Résumé

Comme le pourcentage de la population vieillissante dans les pays industrialisés s’accroît, les préoccupations dermatologiques des personnes âgées augmentent en importance sur le plan médical. Les modifications structurelles intrinsèques sont une conséquence naturelle du vieillissement et sont génétiquement déterminées. La vitesse de vieillissement diffère significativement selon les différentes populations et selon les différents sites anatomiques, même pour un seul individu. La vitesse intrinsèque du vieillissement de la peau pour un individu peut être aussi très influencée par les facteurs personnels et environnementaux, en particulier le taux d’exposition à la lumière ultra-violette. La photodégradation qui accélère considérablement le vieillissement visible de la peau augmente également beaucoup le risque de formation de néoplasme cutané. Au fur et à mesure que la population vieillit, il faut davantage se préoccuper de diminuer la morbidité réelle associée au vieillissement de la peau, plutôt que de palier à ses conséquences cosmétiques. Il est donc crucial de s’efforcer à mieux comprendre les facteurs intrinsèques et extrinsèques qui agissent sur le vieillissement de la peau et aussi de faire la distinction entre les aspects réversibles du vieillissement cutané (facteurs essentiellement hormonaux et mode de vie) et les aspects irréversibles (principalement le vieillissement intrinsèque).


Introduction

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

Ageing is a process in which both intrinsic and extrinsic determinants lead progressively to a loss of structural integrity and physiological function [1]. Intrinsic ageing of the skin occurs inevitably as a natural consequence of physiological changes over time at variable yet inalterable genetically determined rates [2]. Extrinsic factors are, to varying degrees, controllable and include exposure to sunlight, pollution or nicotine, repetitive muscle movements like squinting or frowning, and miscellaneous lifestyle components such as diet, sleeping position and overall health [2].

The demographics of the U.S.A. are changing rapidly with respect to its elderly population; by 2030, one of every five Americans is expected to be over 65 [3]. It is predicted that life expectancy in the U.S.A. and other industrialized countries will continue to increase, hitting 100 years by about 2025 [4]. Women, with longer average life expectancies than men, can expect to spend more than one-third of their lifetimes in menopause [5].

The human integument, one-sixth of the total body weight [6], forms the most visible indicator of age. A sophisticated and dynamic organ, it serves as a barrier between the internal environment and the world outside, yet has numerous functions that go far beyond that role [7] such as homeostatic regulation, prevention of percutaneous loss of fluid, electrolytes, and proteins, temperature maintenance, sensory perception and immune surveillance [6]. The synergistic effects of intrinsic and extrinsic ageing factors over the human lifespan produce deterioration of the cutaneous barrier [1], with significant-associated morbidity. Aged skin is susceptible to pervasive dryness and itching [8], cutaneous infection [9], autoimmune disorders [10], vascular complications [11] and increased risk cutaneous malignancy [8]. In fact, most people over 65 have at least one skin disorder, and many have two or more [12].

One particular cohort of the American population is proving particularly useful in defining the separate roles of intrinsic and extrinsic factors in skin ageing: the ‘baby boomers’, a generation produced by a post-World War II surge in the U.S.A. birthrate between 1945 and 1965. Their arrival coincided with the advent of widespread antibiotic use (as well as universal progress in overall health research), creating the first generation with a third phase of life: the ‘golden years’ with the expectation of leisure time, preservation of youthful appearance and good health [13]. The entrance of the first baby boomers into middle age fuelled the development of commercial products that could reverse the signs of intrinsic skin ageing [13].

At the same time, however, the historically sun-seeking behaviours of these baby boomers have been implicated in a recent surge in skin cancer rates [14]. It is estimated that 90% of all skin cancers are directly related to sun exposure [15]. About 90% of skin cancers are diagnosed at or after the age of 45 [16]. Marked increases in all skin cancer rates have been observed in the last two decades or so, roughly coinciding with the arrival of the baby boomer segment of the population into middle age. Incidence of melanoma has doubled since 1985 [16], while in the last few decades, the incidence of non-melanoma skin cancers has also increased across the Western world by varying but consistently alarming rates. Reported increases in the incidence of basal cell carcinoma in a given recent 10-year period (depending on the study) were as high as 66% (U.K.), although increased incidences as high as 93% (Australia) were reported for squamous cell carcinoma [17]. Annual incidence of these non-melanoma skin cancers exceeds the incidence of any other cancer five fold [17]. It is often the aesthetically unwelcome sequelae of the intrinsic ageing of the skin that bring the patient to the dermatologist’s office. Only 6% of dermatological visits concern skin cancer [2]. Infinitely more damaging to overall health, however, are the extrinsic factors of skin ageing like ultraviolet (UV) light exposure, which, unlike intrinsic factors, can be significantly modified.

Intrinsic skin ageing factors

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

Ethnicity

The greatest effect of ethnicity on ageing is primarily related to differences in pigmentation. High levels of pigmentation are protective with regard to the cumulative effects of photoageing, with African-Americans showing little cutaneous difference between exposed and unexposed sites [18]. In addition, if sensitivity is measured in terms of skin cancer incidence, skin cancer rates between Caucasian and African-Americans indicate that pigmentation provides a 500-fold level of protection from UV radiation [19]. Basal cell carcinoma and squamous cell carcinoma occur almost exclusively on sun-exposed skin of light-skinned people [20].

African-American skin is more compacted than Caucasian skin, as well as having a higher intercellular lipid content, which may contribute to more resistance to ageing [18]. Wrinkling in Asians has been documented to occur later and with less severity than in Caucasians, [21, 22] although the reason for these observations was not explored.

Anatomical variations

Huge variations in some skin parameters have been observed with respect to the body site studied, underscoring a need to standardize study site as well as ages compared in order to obtain meaningful results [23]. There are large differences in skin thickness with respect to body site, ranging from <0.5 mm on the eyelids to more than 6 mm on the soles of the feet [24]. The decrease in epidermal thickness with ageing was found to be smaller at the temple than at the volar forearm [21, 25], which may be the effect of cumulative photoageing.

The lipid composition of human stratum corneum displays striking regional variation in both content and compositional profile [23]. There is a much higher proportion of sphingolipids and cholesterol in palmoplantar stratum corneum than on extensor surfaces of the extremities, abdominal or facial stratum corneum [23]. There is also an inverse relationship between the lipid weight percentage of a particular body site and its permeability [23].

Skin rigidity is much higher at the forehead than at the cheek in post-menopausal women [26]. Also, in areas of the body with high blood flow (e.g. lip, finger, nasal tip and forehead), blood flow decreased with age [27] compared to areas with baseline low blood flow, in which no difference was observed [27]. The decrease in sensory perception with ageing is more pronounced in the nasolabial fold and cheek, than in the chin and forehead [23].

It is commonly assumed that aged skin is intrinsically less hydrated, less elastic, more permeable and more susceptible to irritation [21, 26], because of an apparently less complete functional barrier than that in forearm skin [28] measured by higher transepidermal water loss [21, 28]. Irritant and permeability testing, however, have not demonstrated increased susceptibility [21, 26].

Hormonal changes in cutaneous tissues

The topic of hormonal changes in skin, primarily the effect of changes of oestrogen levels in the skin of women, has been reviewed recently and comprehensively by many competent authors [5, 29–33] and will therefore not be covered here, although we have addressed this topic in other publications [34, 35].

Vulvar skin, however, differs from that of the bulk of cutaneous epithelium in that skin in the vulvar area derives from three different embryonic layers. The cutaneous epithelia of the mons pubis, labia and clitoris originate from the embryonic ectoderm and exhibit a keratinized, stratified structure similar to the keratinized, stratified skin at other sites. The mucosa of the vulvar vestibule originates from the embryonic ectoderm and is non-keratinized. The vagina is derived from the embryonic mesoderm and is responsive to oestrogen cycling [21, 26]. The morphology and the physiology of the vulva and vagina thus undergo numerous specific changes associated with hormonal changes at menopause [26].

After menopause, the following changes occur: vaginal epithelium atrophies, cervico-vaginal secretions become sparse, vaginal pH rises, atrophic vaginitis becomes more common [21, 26], collagen and water content decrease, pubic hair grays and becomes sparse, the labia majora loses s.c. fat and also the labia (labia minora, vestibule and vaginal mucosa) atrophies. In addition, vaginal secretions decrease and the thinned tissue is more easily irritated and susceptible to infection [21, 26].

The cumulative effect of oestrogen deficiency contributes to poor wound healing [5]. Skin collagen content and thickness decrease with the hormonal affects of castration [36]. Also dramatic hormonal changes, particularly thyroid, testosterone and oestrogen, alter epidermal lipid synthesis [23]. Atrophied genital tissue with limited mobility is more susceptible to shear forces and may be more susceptible to pH changes and enzymatic action [21, 26].

Vulvar skin is more resistant to tape stripping and recovers more quickly in younger subjects than in older ones [37]. Also, vulvar skin has an increased rate of epidermal turnover [21, 30] and increased basal cutaneous blood flow [21, 37].

Forearm skin has less frequent and slower reaction to sodium lauryl sulphate irritation than that in younger skin while no age-related differences were observed in the vulvar area [38].

Permeability in the vulva is a complex issue, affected by increased vulvar skin hydration, the presence of hair follicles and sweat glands, cutaneous blood flow, occlusion and the properties of the chemical in question [26]. Testing of vulvar permeability of the aged vulva skin has yielded conflicting results. Absorption of hydrocortisone in the vulva was shown to be greater in aged skin [39], while no age-related differences were observed in percutaneous absorption of testosterone [39]. In general, the vulvar area is more hydrated, with a higher coefficient of friction than other skin [21, 26]. For an extensive review of permeability in the vulva area, see a recent review by Farage et al. [40].

Elderly patients are, however, susceptible to contact irritation dermatitis in the vulvar area, because of urinary moisture under occlusion. Urinary ammonia elevates local pH, which alters barrier function, further compromising skin integrity and increasing risk of infection [21, 26].

The vulvar area, because of sweating, occlusion, vaginal discharge, friction, use of hygiene products and incontinence, is increasingly susceptible to persistent vulval itch and irritation in old age [41, 42].

There is a significant decrease in the size and number of free nerve endings in aged skin in genital mucous membranes with a corresponding decrease in sensory perception in the genital area [21, 43].

Extrinsic skin ageing factors

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

Lifestyle influence

Skin is affected by ambient conditions such as temperature and humidity. An increase in skin temperature of 7–8° doubles the evaporative water loss [44]. Low temperature stiffens skin and decreases evaporative water loss even with plenty of humidity in air, as structural proteins and lipids in the skin are critically dependent on temperature for appropriate conformation [44]. Some medications affect the skin as well, particularly hypocholesterolemic drugs, which may induce abnormal increased desquamation [45].

By far, however, the two greatest exogenous factors, both of which exact a heavy toll on skin, are smoking [46] and exposure to UV light.

Effects of smoking and nicotine

Cigarette smoking is strongly associated with elastosis in both sexes, [47] and telangiectasia (red spots on skin) in men [47]. Smoking causes skin damage primarily by decreasing capillary blood flow to the skin, which, in turn, creates oxygen and nutrient deprivation in cutaneous tissues. It has been shown that those who smoke have fewer collagen and elastin fibres in the dermis, which causes skin to become slack, hardened and less elastic. Smoke causes damage to collagen and elastin in lung tissue and may do so in skin as well [47]. In addition, constriction of the vasculature by nicotine [47] may contribute to wrinkling [36] (Fig. 1).

image

Figure 1.  Effects of smoking on facial skin. Used by permission from Lippincott, Williams and Wilkins.

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Smoking increases keratinocyte dysplasia and skin roughness [1]. A clear dose–response relationship between wrinkling and smoking has been identified [46], with smoking being a greater contributor to facial wrinkling than even sun exposure [47]. Smoking was demonstrated to be an independent risk factor for premature wrinkling even when age, sun exposure and pigmentation were controlled [47]. In addition, although hormone-replacement therapy was demonstrated to reverse wrinkling, the skin of long-time smokers did not respond [36]. The relative risk for moderate-to-severe wrinkling for current smokers compared to that of life-long non-smokers was 2.57 with a CI of 1.83–3.06 and a < 0.0005 [36]. Wrinkle scores were three times greater in smokers than in non-smokers, with a significant increase in the risk of wrinkles after 10 pack-years [48]. Pack-years are calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked [48]. For example, 10 pack-years would define both as smoking one pack a day for 10 years, or two packs a day for 5 years [48]. Smoking also increases free radical formation and is an important risk factor in cutaneous squamous cell carcinoma [47].

Exposure to UV light (photoageing)

Intrinsic changes occur in all skin as people age, including decreased turnover, chemical clearance, thickness and cellularity, thermoregulation, mechanical protection, immune responsiveness, sensory perception, sweat and sebum production and vascular reactivity [21, 49]. These changes represent a generalized atrophy with few structural alterations up to the age of 50, followed by slow deterioration [44]. In contrast, solar exposure to UV light initiates a flurry of molecular and cellular responses that end with a rapid dynamic disorder [44].

The effects of sunlight on the skin are profound, and are estimated to account for up to 90% of visible skin ageing [21, 22], particularly in those without the natural protection associated with higher levels of melanocytes in the skin [18]. Sunlight is composed of three different types of radiation: UVC, UVB and UVA. UVC (100–290 nm) is largely blocked by the ozone layer and has little impact on skin [20]. UVB (290–320 nm) penetrates only into the epidermis and is responsible for the erythema associated with a sunburn [20]. UVA requires 1000-fold higher levels of radiation to cause sunburn, so it was long considered irrelevant to skin damage. It is now known that because it penetrates into the dermis, UVA may be responsible for most of the chronic skin damage associated with photoageing [20].

Sunlight damages skin across a spectrum of physiological processes. UV radiation in the dermis causes a molecular chain reaction which ultimately results in the upregulation, in both dermis and epidermis, of matrix metalloproteinases which stimulate the production of collagenase, gelatinase and stromelysin-1 in both fibroblasts and keratinocytes. The result is a deterioration of both collagen and elastin, as well as other components of the dermal extracellular matrix. Repeated exposure to solar radiation yields repeated, and increasingly faulty, attempts to repair the dermal matrix, with a cumulative effect on the structure and organization of its collagenous foundation. Invisible flaws in the repaired dermal matrix, with repeated cycles of exposure, eventually become visible to the naked eye in the form of sagging skin and wrinkles [50].

Ultra violet radiation also initiates damage to the genetic material. UVB primarily acts to create pyrimidine dimers that eventually result in mutation through errors in DNA replication; UVA radiation primarily initiates genetic damage through the creation of reactive oxygen species or free radicals [51]. Free radicals can also wreak havoc on numerous cellular processes, e.g. facilitating the upregulation of matrix metalloproteinases (discussed above) [51].

In addition, UV radiation acts indirectly to damage skin by interfering with enzymes critical to the DNA repair process, and by interference with components of the immune system (specifically T cells and Langerhans cells) that act to eradicate carcinogenic cells [20]. It has recently been shown that UV radiation may also act to prevent apoptosis in sun-exposed cells, thereby potentially promoting tumour development [52].

In this respect, UV radiation is a complete carcinogen, as it both initiates cancer through DNA mutation and promotes cancer growth through the inflammatory processes inherent in cumulative UV exposure (Fig. 2) [21, 53].

image

Figure 2.  Surface melanoma.

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Photoageing is the superposition of this solar damage on the normal ageing process, defined specifically by damage produced in tissue by single or repeated exposure to UV light, believed to account for the vast majority of not only aesthetic effects of skin ageing, but also clinical problems as well [21, 49]. Modern Western culture has promoted tanned skin as healthy, resulting in steadily increasing rates of skin cancer and prematurely aged skin [21, 41]. Virtually all Caucasian Western individuals with normal recreational practices have subclinical signs of skin damage by the time they are 15 years old [53], whereas skin changes start to become discernible in unexposed skin in the early 30s [2, 21].

Ultraviolet light induces photochemical changes that can lead to either acute effects (e.g. erythema or sunburn) or chronic effects (e.g. premature skin ageing and neoplasms) [21, 41]. The clinical signs of cutaneous photoageing include changes in visible colour, surface texture [21, 41] including early appearance of dyschromia and lentigines, sallow yellow colour, loss of normal translucency or pink glow, gradual appearance of telangiectasia and purpura [21, 41]. Textural changes include increased roughness, frank keratoses and the development of fine rhytides which progress to deeper folds and creases [21, 41].

Corneocytes in sun-exposed areas become pleomorphic with increasing anomalies: retention of nuclear remnants, loss of lines of overlap and roughening of border edges [2, 54]. Also, UV radiation alters the skin’s immune function systemically [20, 21]. Epidermal thickness increases, then decreases, with an eventual loss of epidermal polarity (orderly maturation) and increased atypia among individual keratinocytes [20, 21].

Ultraviolet band A (UVA) light penetrates more deeply. Although it does not cause pronounced erythema, it may damage dermis more than UVB light, particularly elastic tissue related to skin ageing [44]. Changes in the dermis include the degeneration of collagen and deposition of abnormal elastotic material, seen as wrinkles, furrows and yellowing of skin [20, 21]. With severe photodamage, the dermis becomes a massive quantity of thickened, tangled and degraded elastic fibres. Tightly packed collagen fibrils replace elastic microfilaments, becoming finally an amorphous mass [20, 21]. Damaged dermal tissue provides less support to its vascularization, causing vessels to widen and become visible at the skin surface as telangiectasia [44]. The decrease in perfusion in aged skin is more pronounced in photoaged areas [44]. It has recently been reported that it may be UVA that is responsible for the bulk of epidermal skin damage. UVA excitation of trans-urocanic acid initiates chemical processes that result in photoageing of the skin [55].

Although the primary effect of photodamage is skin thickening, severe damage results more in dramatic thinning [20, 21]. Sun damage creates a state of chronic inflammation, with ongoing release of proteolytic enzymes by inflammatory cells, disrupting the dermal matrix [20, 21]. Irradiated skin was observed to have a decreased capacity for inflammatory response [21, 43]. UV light also reduced the quantity of epidermal Langerhans cells, while it induced proliferation of suppressor T cells, facilitating tumour induction [21, 43]. Although plasma concentration of retinol increases with age, within the epidermis, vitamin A is destroyed by sun exposure [56].

With acute sun exposure, genes with reparative, protective or apoptotic functions as well as stress communication genes are rapidly activated [19, 57, 58]. Ageing strikingly increases the expression of related genes when exposed to UV [59].

Ultraviolet exposure modulates expression of collagen I, III and VI genes; heat shock protein 47 (Hsp47) genes and matrix metalloproteinase 1 (MMP 1), contributing to the general disruption of skin structure. Collagen I is time- and age-dependent, where it is reduced after a single UV exposure in human skin in vivo [21, 22]. Photoageing is associated with increased expression of MMP 1 and MMP 9 [21, 60].

Characteristics of photoageing when compared to intrinsic ageing are in Table I.

Table I.   Comparing photoageing to intrinsic ageing
CharacteristicPhotoageingIntrinsic ageingReference
  1. Numbers in parentheses refer to citations in the reference list.

Overall
 Metabolic processesPronounced increaseSlow downSoter [61]
 Clinical appearanceNodular, leathery, blotchySmooth, unblemishedGlogau [62]
 Coarse wrinkles, furrowsLoss of elasticity, fine wrinklesGlogau [62]
 Skin colorIrregular pigmentationPigment diminishes to pallorRees [63]
 Skin surface markingMarkedly altered, often effacedMaintains youthful geometric patternsGilchrest [20]
 OnsetAs early as late teensTypically 50s–60s (women earlier than men)Kligman [64]
 SeverityStrongly associated to degree of pigmentationOnly slightly associated to degree of pigmentationRees [19]
Epidermis
 ThicknessAcanthropic in early stagesThins with ageingTakema [65]
Atrophy in end stages Lavker [66]
 Proliferative rateHigher than normalLower than normalLavker [66]
 KeratinocytesAtopic and polarity loss numerous dyskeratosesModest cellular irregularityKligman [67]
 Dermo–epidermal junctionExtensive reduplication of lamina denseModest reduplication of lamina denseGilchrest [20]
 Vitamin A contentDestroyed by sun exposurePlasma content of retinol increasesSeite [58]
Dermis
 ElastinMarked elastogenesis followed by massive degeneration, dense accumulations on fibresElastogenesis followed by elastolysis –‘moth-eaten fibres’Kligman [67]
 Elastin matrixMassive increase in elastic fibres, replacing the collagenated dermal matrixGradual decline in production of dermal matrix, only modest increase in the number and thickness of elastic fibres in the reticular dermisHanson [56]
 Lysosyme deposition on elastic fibresIncreasedModestGilchrest [20]
 Collagen productionDecrease in amounts of mature collagen Mature collagen more stable in degradationLavker [66]
 Grenz zoneProminentAbsentLavker [66]
 MicrovasculatureAbnormal deposition of basement membrane-like materialNormalGilchrest [20]
 MicrocirculationVessels become dilated, derangedMicrovessels decrease, remaining vessels do not changeGilchrest [20]
 Inflammatory responsePronounced inflammation, perivenular, histocytic-lymphocytic infiltrateNo inflammatory response observedGilchrest [20]

Conclusion

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

As the senior segment of the population increases, the challenge of gerontological dermatologists will be to move beyond the current focus on the unwelcome aesthetic aspects of skin ageing to an amelioration of the significant discomfort produced by the ageing of the human integument [45]. The ability of exogenous oestrogen to halt and even reverse the numerous external effects of skin ageing in post-menopausal women speaks to the potential-to-affect genuine improvement [5]. Useful therapies, however, will require a deeper understanding of the influences of both intrinsic and extrinsic factors on the molecular processes of cutaneous ageing.

Intrinsic ageing, though genetically determined and inalterable, is not constant across different populations or even different anatomical sites on the same individual. However, the potential components of extrinsic ageing, including nutrition, tobacco use and exposure to solar rays, are virtually endless, thus resulting in a wide range of visible signs of aged skin even within genetically similar individuals of the same age. Future research will strive for better understanding of both intrinsic and extrinsic influences on the ageing of the skin, while defining the retractable aspects of cutaneous ageing (primarily hormonal and lifestyle influences) as opposed to the irretractable (primarily intrinsic ageing). Optimally, clinicians will seek to lessen the effects of intrinsic ageing while at the same time aim for avoidance of the extrinsic components with a commitment to: (i) accept the factors that cannot be changed, (ii) treat the factors that can be treated and (iii) have the evidence-based ‘wisdom’ to know the difference.

Acknowledgements

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References

The authors are grateful to Drs S. McClanahan, Randy Nunn, Keith Ertel, Don Bissett, Joe Kaczvinsky for the critical review of this manuscript and to Ms Zeinab Schwen and Ms Wendy Wippel (Strategic Regulatory Consulting, Cincinnati, OH, USA) for technical preparation. This work was fully funded by P&G.

References

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Intrinsic skin ageing factors
  5. Extrinsic skin ageing factors
  6. Conclusion
  7. Acknowledgements
  8. References