structural characteristics of the aging skin: a review

STRUCTURAL CHARACTERISTICS OF THE AGINGSKIN: A REVIEW

Miranda A. Farage and Kenneth W. MillerThe Procter & Gamble Company, Winton Hill Business Center, Cincinnati,Ohio, USA

Peter ElsnerKlinik Fur Dermatologic, Jena, Germany

Howard I. MaibachUniversity of California, Department of Dermatology, San Francisco,California, USA

As life expectancy in industrialized countries increases, appropriate care of elderly skin

looms as a dermatologic priority. Skin aging is a complex, multifactorial process whose

baseline rate is genetically determined but that may be accelerated by environmental, mech-

anical, or socioeconomic factors. The intrinsic structural changes that occur with the aging

of the skin increase skin fragility, decrease the ability of the skin to heal, increase risk for

toxicological injuries, promote the development of various cutaneous disorders, and produce

aesthetically undesirable effects like wrinkling and uneven pigmentation. As aged patients

represent a larger segment of the population, increased attention to the problems of the aged

skin, both cosmetic and beyond, will be necessary and should build on currently successful

interventions to improve their quality of life.

Keywords: Aging population; Aging skin; Barrier function; Collagen; Dermis; Elastin; Skin thickness

INTRODUCTION

In 1900, life expectancy in the United States was just 50 years, with only 4% ofthe American population over the age of 65 (1). By the year 2000 (largely due tobetter diet and medical care) (2) that percentage had tripled, with life expectancycurrently averaging 77.6 years overall (2) (Figure 1). It is predicted that life expect-ancy in the U.S. and other industrialized countries will continue to increase, hitting100 years by about 2025 (3). Women, with longer average life expectancies than men,can expect to spend more than one-third of their lifetimes in menopause (4). As theaged population continues to increase in numbers, the various implications ofcutaneous aging will increase in medical importance.

Address correspondence to M. A. Farage, Ph.D., The Procter and Gamble Company, Winton Hill

Business Center, 6110 Center Hill Road, Box 136, Cincinnati, OH 45224, USA. Tel.: +1 513 634 5594;

Fax: +1 513 634 7364; E-mail: [email protected]

343

Cutaneous and Ocular Toxicology, 26: 343–357, 2007

Copyright # Informa Healthcare USA, Inc.

ISSN: 1556-9527 print=1556-9535 online

DOI: 10.1080/15569520701622951

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Aging is a complex, multifactorial phenomenon involving both intrinsic andextrinsic parallel processes that contribute progressively to a loss of structural integrityand physiological function of the skin that leads, inevitably, to death. Aging proceedsat intrinsically different rates, driven by genetic regulation, the toxicity of certain by-products of metabolism and a lack of sufficient physiological resources dedicated tosomatic maintenance and repair (5). Factors contributing to aging can be divided intofour main categories: biological (genetically determined and inalterable), environmen-tal (damage associated with exposure to sunlight, pollution or nicotine), mechanicalaging (repetitive muscle movements such as squinting or frowning), and miscellaneousfactors including diet, sleep patterns, morbidity, and mental health (5).

Although skin is incredibly durable, it is affected, like all other organ systems,by aging (6). The synergistic effects of intrinsic and extrinsic aging factors over thehuman lifespan combine to cause deterioration of the cutaneous barrier andthe structural integrity of the skin (7). Hormonal changes that also play a role inthe aging of skin, especially in females, lead to earlier signs of aging for women (8).

Most skin aging therapies aim at reversing aesthetically unwelcome signs. However,skin aging can also produce significant morbidity, pervasive dryness and itching (9) andincreased risk of numerous skin diseases, including cutaneous malignancy (9). In fact,most people over 65 have at least one skin disorder, and many have two or more (10).

Defining the retractable aspects of cutaneous aging (primarily hormonal andlifestyle influences) from the irretractable (primarily intrinsic aging) is essential tothe understanding of the aging skin. As the population ages, the dermatologic focus

Figure 1 Mean life expectancy in the United States by year from the National Vital Statistics Report

(NVSS) from the Centers for Disease Control, U.S. Department of Health and Human Services. November

10, 2004.

344 M. A. FARAGE ET AL.

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must shift from cosmetic interventions to improving morbidity and quality of life forthis growing segment of the population (11). The structural changes of the aging skinwill be discussed in this article, whereas the physiological changes and lifestyle influ-ences on the skin will be reviewed separately.

STRUCTURE AND FUNCTION OF NORMAL SKIN

The human integument, one-sixth of the total body weight (12), forms the mostvisible indicator of age. A sophisticated and dynamic organ, serving as a barrierbetween the internal environment and the world outside, yet has numerous functionsthat go far beyond that role (13) including: homeostatic regulation, prevention ofpercutaneous loss of fluid, electrolytes, and proteins; temperature maintenance; sen-sory perception; and immune surveillance (12).

The skin is commonly subdivided into three layers: epidermis, dermis, andhypodermis (Figure 2).

Epidermis

The epidermis (the external skin surface), although widely variable, typicallymeasures 50 mm to 100 mmin thickness (14). This layer contains primarily keratino-cytes, with smaller populations of Langerhans cells and melanocytes (Figure 2)(11). Although slight variation is reported in the literature, the keratinocyte popu-lation in the epidermis is completely replaced approximately every 30 days (15).

The epidermis is a dynamic system whose metabolic activity is largely regulatedby the integrity of the permeability barrier (11), which is responsible for maintainingthe fine balance between clinically normal and dry skin (8). This function resides in

Figure 2 Normal skin structure showing layers of dermis and epidermis.

STRUCTURAL CHANGES OF AGING SKIN 345

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the outermost layer of the epidermis, the stratum corneum (16). The stratum corneumis a dynamic, metabolically interactive tissue (16) comprised of about 60% structuralproteins, 20% water, and 20% lipids (11,17). Its integrity depends on its lipid compo-sition,16 primarily cholesterol, ceramides, and free fatty acids (11,16).

The dynamic nature of the stratum corneum makes it vulnerable to derange-ment of barrier function (11). Skin is considered clinically dry when the moisturecontent falls below 10%, at which point the stratum corneum becomes less flexibleand begins to crack or fissure (8). Dehydration can result in a reduced capacity toinhibit entry of pathogenic microbes (11).

Dermis

The dermis, 2 to 3 mm in thickness, is a layer composed predominantly of con-nective tissue and blood vessels, that comprises the main bulk of the skin (4) (Figure 2),supports the epidermis, and binds it to the hypodermis (12). Dermal connective tissuecontains elastin and collagen; collagen fibers comprise the biggest volume of the skinand the bulk of its tensile strength (4), whereas elastin fibers contribute to elasticityand resilience (4). The dermis also contains nerve fibers, sensory receptors, hyaluronicacid (responsible for normal turgor of dermis because of extraordinary water-holdingcapacity), and supportive glycosaminoglycans (GAG) (4).

Hypodermis

Below the dermis is the hypodermis, a layer of loose connective tissue thatbinds the skin to internal organs. This layer contains subcutaneous fat as well as are-olar tissue, providing cushioning, thermoregulation, and skin stability by connectingdermis to internal organs (18).

STRUCTURAL CHANGES IN AGED SKIN

As the skin ages, changes are seen in skin thickness and quality of the epidermisand dermis as discussed later (Figure 3 and Table 1).

Recent technical progress has allowed more objective and precise characteriza-tion of the aging human skin (19). Great progress has been made in noninvasive, invivo imaging of the skin (20), and improved bioengineering methods allow moreaccurate analysis of its mechanical properties.

Ultrasound echogenicity studies yield images that provide information onchanges in ultrastructural features of skin (19). Laser Doppler Velocimetery(LDV) analyzes cutaneous blood perfusion (19). LDV penetrating as deep as1 mm yields data on deeper vessels not visible by capillaroscopy methods. Twonew microscopy procedures allow direct measurement on unmodified skin. Confocallaser scanning microscopy (CLSM) (18–20) does not penetrate the skin, but canvisualize individual cells, measuring images parallel to skin surface (18,20). Althoughoptical coherence tomography (OCT) (18,20) enables imaging of skin as deep as2 mm, it cannot resolve individual cells (18,20). Pulsed ultrasound, which can be usedon any site, is useful for determination of whole skin thickness (19).


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Skin Thickness Changes

The skin, which thickens over the first 20 years, thins progressively over adultlife at a rate that accelerates with age (19), even though the number of cell layersremains stable (21).The epidermis decreases in thickness (9) with age; this changeis most pronounced in exposed areas, including the face, neck, upper part of thechest, and the extensor surface of the hands and forearms (22). Epidermal thickness

Figure 3 Differences in skin structure between normal and aged skin.

Table 1 Changes in the structure of aged skin

Skin structure Observed effect of aging Reference

Stratum corneum Lipid content decreased Saint Leger et al. (53)

Epidermis Flattening of dermal-epidermal junction Neerken et al. (20)

Number of enzymatically active melanocytes

decreases by 8% to 20% per decade

Rees (14)

Number of Langerhan’s cells decreases Fenske & Lober (6)

Capacity for re-epitheliazation diminishes Orenteich & Selmanowitz (54)

Dermis Decrease in thickness (atrophy) Waller & Maibach (19)

Vascularity decreases as does cellularity Duncan & Leffell (31)

Decrease in collagen synthesis Phillips & Kanj (26)

Pacinian and Meissner’s corpuscles degenerate Phillips & Kanj (26)

Structure of sweat glands becomes distorted,

numbers of functional sweat glands decreases

Phillips & Kanj (26)

Elastic fibers degrade McCallion & Li (8)

Decrease in number of blood vessels Duncan & Leffell (31)

Hypodermis Change in distribution of subcutaneous fat Phillips & Kanj (26)

Appendages Hair loses normal pigments Phillips & Kanj (26)

Hair thins Phillips & Kanj (26)

Decrease in sweat glands Phillips & Kanj (26)

Abnormal nail plates Phillips & Kanj (26)


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decreases about 6.4% per decade (19,23), and decreases even faster in females.Dermal thickness also decreases, but at the same rate in both genders (8).

Epidermal Changes

Cell numbers in the epidermis are reduced in older adults (24). Keratinocytes,as skin ages, change shape, becoming shorter and fatter (24) whereas corneocytes inaged skin become bigger as a result of decreased epidermal turnover (21,25). Epider-mal turnover time is increased in aged skin (6,18).

Enzymatically active melanocytes decrease at a rate of 8% to 20% per decade,resulting in uneven pigmentation in elderly skin (26). A parallel decrease in the num-ber of Langerhan’s cells leads to impairment of cutaneous immunity (26). An atypiain cells of the basal layer is also observed (19) Although the number of sweat glandsdoes not change, sebum production decreases (26) whereas a reduction of the naturalwater and fat emulsion on the skin is observed (27). Water content in aged dry skin,particularly in the stratum corneum, is lower than that of younger skin (8,9,11).Aging skin dries, with a greater tendency to xerosis (9). Changes in the amino acidcomposition in aged skin (8) also reduce the amount of cutaneous natural moisturiz-ing factor (NMF), thereby decreasing its water binding ability (11).

Barrier Function

Because permeability barrier function in aging epidermis does not appear to beimpaired under basal conditions, it has been generally assumed that barrier functiondoes not alter significantly with aging (28). Baseline transepidermal water loss(TEWL), however, decreases with age (9,28) an observation believed to be due tothe reduction of the water content of aged skin. In other words, the elderly lose lessbecause they have less water to lose. The authors of this study did not, however,adjust results for mass (28). Recovery of baseline TEWL values after occlusion isslower in older skin (9).

Further studies revealed that aged skin was much more easily disrupted bytape-stripping than was younger skin (28), requiring only 18 strippings in individualsover 80 years of age as compared to 31 strippings in young and middle-aged adults.Recovery of barrier function in the aged subjects was also dramatically different.Only 15% of those older than 80 had recovered barrier function at 24 h, comparedto 50% of the younger group (28). Artificially induced water gradients (such as pro-duced by occlusion) were shown to dissipate more slowly in older skin than inyounger (11), with occluded older skin having a significantly higher TEWL thanyounger skin as well (11). Depending on the compound and the anatomic site eval-uated, significant differences in barrier permeability have been observed (23).

The findings reveal a profound change in barrier integrity even though barrierfunction under normal conditions appears normal. Baseline TEWL measurementsthen, because they do not reflect actual functional status, can be misleading (28).A lack of functional reserve is exposed when the epidermal permeability barrier isunder stress (28). Interestingly, one study found that with the drying skin character-istic of intrinsic aging, TEWL and the water content of the stratum corneum drop in


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parallel, while in pathological conditions, TEWL increases even though stratumcorneum water content stays low. In stripped skin, both values increase (29).

Lipid Composition

Although the lipid composition of the aged skin is not significantly altered, theglobal lipid content of the aged skin is reduced (14,28). Total lipid content in agedskin decreased as much as 65% (24). An age-related decrease in the amount of lipidin the stratum corneum was also observed as well (9). An age-related decrease in thesterol ester and triglyceride fraction of stratum corneum lipids was also observed (9).Also, histological studies reveal that the number of papillae per area decreases dra-matically (27), from an average of 40 in young skin, down to 14 papillae=mm2 inthose aged over 65 (30).

Dermal–Epidermal Junction

The most reproducible structural change in aged skin is a flattening of thedermal–epidermal junction occurring as a result of rarification and reduction ofdermal papillae (30).This flattening, seen in scanning electron images at about thesixth decade (19), creates a thinner epidermis primarily because of retraction of retepegs (19), leading to an increase in the minimal thickness of epidermis with a concur-rent decrease in maximum thickness (18,20). As a result, the dermal–epidermaljunction flattens by 35% (18,20).

The flattened dermal–epidermal junction, with its reduced interdigitationbetween layers, results in less resistance to shearing forces and an increased vulner-ability to insult (21). The smaller contiguous surface between the two layers createsreduced communication between the dermis and epidermis and a reduced cellularsupply of nutrients and oxygen (18,30). Flattening also may be associated withdecreased potential for proliferation and may affect percutaneous absorption (19).

The flattening of the dermal–epidermal junction also increases the potential fordermo-epidermal separation, facilitating wrinkle formation (21), a process that maybe a mechanism by which wrinkles form (18,30).

Dermal Changes

Dermal thickness decreases with age (19), with a decrease in vascularity andcellularity (31). The perception of pressure and light touch stimuli also decreases,due to a degeneration of pacinian and Meissner’s corpuscles. There is also a decreasein the number of mast cells and fibroblasts (31). The amount of glycosaminoglycansin the dermis declines with age (18,30), as does the amount of hyaluronic acid pro-duced by fibroblasts (18,30) and the amount of interfibrillary ground substance (32).

Skin stiffness remains fairly constant until it decreases in the eighth decade oflife (33). Aging, however, is inevitably associated with a decrease in collagen turn-over (due to a decrease in fibroblasts and their collagen synthesis) as well as elastin(31). Elastin also has higher degree of calcification in aged skin, with an associateddegradation of elastin fibers (22). Collagen cross-links stabilize, whereas collagenbundles become disorganized (31).


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The loss of molecular integrity of the dermis leads to increased rigidity,decreased torsion extensibility (6,18) and diminished elasticity (4,8) (eroding fasterin females than in males) (8), with a concomitant increase in vulnerability to tear-type injuries (6,18). Recovery from mechanical depression, in fact, is dramaticallyaltered; observed in only minutes in young skin, but requiring more than 24 h in skinof aged individuals (6,18).

Confocal laser scanning microscopy (CLSM) and optical coherence tomogra-phy (OCT) provides in vivo, cross-sectional images of skin layers. Images of agedskin display a definite decrease in the maximal thickness of the epidermis as wellas a flattening of the dermal–epidermal junction (18,20). Below the basal layer,CLSM showed a reflecting layer of fibrous structure (18,20). The location of thelayer was strongly associated with age, found much deeper in younger than in olderskin (18,20). OCT also showed a bright reflecting age-associated fibrous layer in thedermis, believed to be the same layer, which may be a transition between papillaryand reticular dermis (18,20).

Ultrasound echogenicity revealed that although overall dermal echogenicitydecreases with age (19) there is a regional enhancement in lower dermis echogenicity,called the dermal echogenic band (DEB), that thins with aging (19). In addition, asubdermal low echogenic band (SLEB or SENEB), not seen in young skin, wasobserved in aged individuals. This band increased in width in proportion toage and sun exposure and was found to correspond to an area histologicallydefined as elastoic, in a region especially prone to accumulate increased amountsof water (19).

Hypodermal Changes

The overall volume of subcutaneous fat typically diminishes with age, althoughthe proportion of body fat increases until approximately age 70. Fat distributionchanges as well; that in the face, hands, and feet decreases whereas a relative increaseis observed in the thighs, waist, and abdomen. These changes, while possibly increas-ing thermoregulatory function by further insulating organs, decrease the cushioningfunction in the extremities, which leads to an increased risk of bedsores or podiatricproblems (26).

Toxicological Implications of Structural Changes

The cumulative structural changes that come with age, combined with a life-time of cutaneous insult, make the elderly more likely than younger individuals tohave a wide range of toxicological issues with their skin (Table 2). In addition, eld-erly patients often have impaired sensory function as well as dementia and loss ofmemory, which can increase risk for toxicological injuries (34,35) For example, ithas been observed that in the elderly retention of oral instructions during an officevisit is often less than 50% (36), making accidental overdose of medications morelikely.

Treatments that are routine in younger patients may require modification inthe elderly (37) due to the elderly patient’s diminished ability to heal or cope withskin failure (38). Traditional second-line therapies may be called for in early stages


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of treatment (35). Safety concerns with any medication are accentuated in theelderly, due to the more fragile nature of their integument, the tendency for pro-longed use in chronic skin conditions, the possibility of drug eruptions (39), andthe probability of polypharmacy in this population (38). Stronger medicationsshould be chosen only when therapeutic benefit justifies the risk (40).

Contact dermatitis is common in the elderly population (41), particularlyallergy-type reactions (42). Reduced ability to mount a delayed-type hypersensitivityreaction (43) in the elderly decreases individual susceptibility to allergic contactsensitivity due to a reduction in numbers of Langerhans cells (44), decreased T-cells,and diminished vascular reactivity (43). However, decades of potential sensitization(39) and an increased level of exposure maintains a presence of allergic contactsensitivity in the geriatric population (44,45). The most common culprit in allergiccontact sensitivity is topical medications (46), in fact, as much as 81% of patientsbeing treated for chronic leg ulcers exhibit allergic reactions to topical medications(44). Patch testing before the use of topical medications may be beneficial, especiallywithin high-risk populations like those being treated for dermatitis or ulcerationof the lower extremities (39). Testing should include medicaments and dressings,as well as dental prostheses and medications for ocular disease (39). In the aged,generalized allergic rash is far more likely to be due to medicines than to be food-related (39). Occasionally an agent increases the patient’s sensitivity to the sun ina phototoxic (photoirritant) reaction, or produces a hypersensitivity reaction uponsun exposure (46).

ANTI-AGING THERAPIES

Estrogen Replacement Therapy (ERT)

The advent of ERT for menopausal women has documented clearly the pro-found influence of endogenous estrogen on the skin. Exogenous estrogen, adminis-tered to postmenopausal women, has demonstrated the ability to reverse or preventmany of the processes of intrinsic skin aging.

In clinical trials, women on ERT consistently had greater skin thickness thanthose not using ERT (4). A cross-sectional study using diagnostic ultrasound demon-strated that the use of ERT normalized skin thickness levels to premenopause levels(4). Although the increase in skin thickness was credited to an increase in dermalconnective tissue rather than epidermis, topically applied estradiol cream was shownto produce an increase in epidermal thickness of 23% as well as a normalization ofrete peg patterns (4).

The reduction in dermal collagen associated with postmenopausal estrogendeclines is believed to be the main component of the skin atrophy that occurs withaging, with a 30% loss in collagen occurring over the first five menopausal years (4).Numerous studies, reviewed by Hall (2004) and Brincat (2005) and colleagues, havedemonstrated an increase in the collagen content of the dermis with the use ofexogenous estrogen replacement, with increases as substantial as 6.5% (4,47).Studies have also demonstrated improvements in elasticity and skin laxity withERT, as well as substantial improvement in wrinkling, at least in women who didnot smoke (47).


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Topical Anti-Aging Treatments

With respect to interventions focused specifically on the cosmetic issues ofaging skin, topical medicines predominate for obvious reasons and have includedsex hormones, vitamins, and various topically applied skin components (48). Topi-cally applied estrogen reverses many effects of both intrinsic and photoaging (4),as does progesterone (18,49).Vitamin C (20) and A (20) (especially its derivative, reti-nal) have also been employed with significant success. Topical application of an iso-flavone emulsion derived from soy was demonstrated to reverse the loss of dermalpapillae at the dermal–epidermal junction (18,30) as well as significantly enhancenumber of dermal papillae in age-atrophied skin (18,30).

Clinical testing of a topical vitamin B3 preparation, niacinamide, has demon-strated significant efficacy against numerous undesirable consequences of aging skin.Fifty Caucasian females between the ages of 40 and 60 were treated for 12 weeks in asplit-face study with a moisturizer with and without the addition of 5% niacinamide.Niacinamide-treated skin showed significant improvement with regards to fine lines=wrinkles, hyperpigmentation spots, texture, red blotchiness, and sallowness as com-pared to skin treated with moisturizer alone (50). A facial moisturizer containing nia-cinamide in combination with panthenol and vitamin E was also shown, in a 4-weekrandomized, blinded, controlled study, to improve stratum cornum barrier function,rehydrate skin, and improve the clinical signs and symptoms of rosacea (51).

Epidermal Stem Cells

Epidermal stem cells, the field of most interest in current anti-aging researchhave recently been localized in the interfollicular epidermis. Frequency of theselong-term repopulating cells is approximately 0.01% of basal epidermal cells; how-ever, 100-fold fewer than previously believed (52).

CONCLUSION

Despite the numerous and profound changes that occur over a skin’s lifetime,the human integument remains relatively functional, particularly when protectedfrom environmental insult. Compared to youthful skin, however, the skin of oldersubjects is compromised in many ways (9). Structural changes lead to undesirablevisible characteristics as well as a decreased elasticity and resilience, leaving the agedskin susceptible to injury and disease.

As the population of the industrialized world continues to age, increased atten-tion to the problems of aged skin, cosmetic and beyond, will improve the quality oflife in those years gained by previous medical accomplishments.

ACKNOWLEDGMENTS

The authors are grateful to Drs. S. McClanahan, Randy Nunn, Keith Ertel,Don Bissett, and Joe Kaczvinsky for the critical review of this manuscript, toMs. Zeinab Schwen and Ms. Wendy Wippel (Strategic Regulatory Consulting,


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Cincinnati, OH) for assistance in the preparation of this manuscript, and toMs. Peggy Firth for the medical illustrations.

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structural characteristics of the aging skin: a review

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