Cutaneous aging includes two distinct phenomena. Intrinsic aging is a universal, presumptively inevitable change attributable to the passage of time alone; extrinsic aging is the superposition on intrinsic aging of changes attributable to chronic environmental insults, sun exposure, which are neither universal nor inevitable. Extrinsic skin aging is also commonly termed photoaging, reflecting the large and well-studied role of chronic sun exposure. The former is manifested primarily by physiologic alterations with subtle but undoubtedly important consequences for both healthy and diseased skin. The latter has major morphologic as well as physiologic manifestations and corresponds more closely to the popular notion of old skin.
The skin changes that occur with aging (Table 109-1) lead to a gradual physiologic decline (Table 109-2).33 Major age-related changes in the skin's appearance include dryness (roughness), wrinkling, laxity, and a variety of benign neoplasms. Aged skin is inelastic and recovers more slowly after injury.
Table 109-1 Histologic Features of Aging Human Skin ||Download (.pdf)
Table 109-1 Histologic Features of Aging Human Skin
Flattened dermal–epidermal junction
Atrophy (loss of dermal volume)
Loss of hair
Conversion of terminal to vellus hair
Variable cell size and shape
Fewer mast cells
Abnormal nail plates
Occasional nuclear atypia
Fewer blood vessels
Shortened capillary loops
Fewer Langerhans cells
Abnormal nerve endings
Table 109-2 Functions of Human Skin that Decline with Age ||Download (.pdf)
Table 109-2 Functions of Human Skin that Decline with Age
|Vitamin D production|
Mechanisms of Intrinsic Skin Aging
A major aging theory34 suggests that cumulative damage to biomolecules, including DNA as a result of continuous generation of free radicals, results in increased cellular vulnerability and eventually terminates in senescence or apoptosis. The skin, like other bodily systems, is continuously exposed to ROS generated during aerobic metabolism (eFig. 109-0.1). Although the skin contains a network of antioxidant enzymes (superoxide dismutases, catalase, and glutathione peroxidase) and nonenzymatic antioxidant molecules (vitamin E, coenzyme Q10, ascorbate, and carotenoids), this system is less than completely effective and tends to deteriorate with aging.35
Mechanisms of skin aging. Reactive oxygen species (ROS) generated during aerobic metabolism activate the transcription factor nuclear factor κB (NF-κB) that induces the expression of the proinflammatory cytokines, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-β. ROS also lead to the formation of carbonyl groups (C = O) in proteins, leading to the accumulation of damaged proteins. Ultraviolet (UV) irradiation directly activates cell surface receptors (indicated by symbols on the cell membrane), initiating intracellular signaling that eventually activates the nuclear transcription complex AP-1. AP-1 increases transcription of matrix metalloproteinases (MMPs) and decreases expression of the procollagen I and III genes and transforming growth factor (TGF)-β receptors, with a final consequence of reduced dermal matrix formation. UV also activates the NF-κB transcription factor that induces the expression of multiple proteins and aggravates the degradation of dermal matrix by increasing MMP levels. Matrix degradation is further exacerbated by MMP-8 (collagenase) of neutrophil origin, following neutrophil infiltration into UV-irradiated skin. Mitochondria display large DNA deletions and compromised function. Damaged proteins containing carbonyl groups accumulate in the upper portions of the dermis. (From Halachmi S, Yaar M, Gilchrest BA: Advances in skin aging/photoaging: Theoretic and practical implications (Part I). Ann Dermatol Venereol 132:362, 2005, with permission.)
Oxidative stress upregulates the level of stress regulatory proteins, including hypoxia-inducible factors (HIFs) and nuclear factor κB (NFκB). HIFs influence the expression of genes that regulate cellular metabolism, survival, motility, basement membrane integrity, angiogenesis, hematopoiesis, and other functions.36 Both HIFs and NFκB induce the expression of proinflammatory cytokines like interleukin (IL)-1 and IL-6, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-α. These proteins are involved in immunoregulation and cell survival,37 stimulate the expression of matrix-degrading metalloproteins,38 and are believed to play a central role in the aging process. Furthermore, HIFs stabilize subpopulations of malignant cells with stem cell properties (cancer stem cells) and induce their self-renewal by stimulating the expression of signaling pathways critical for survival and proliferation. This suggests that age-associated cellular hypoxia could be involved in cancer stem cell maintenance.36
Oxidative damage also affects telomeres. A recent hypothesis suggests a common cellular signaling pathway activated by DNA damage and involving the terminal portion of the telomeres.39,40 The terminal portion of the 3′ telomeric strand extends beyond the complementary 5′ strand (Fig. 109-1), leaving a single stranded G-rich overhang. It is suggested that during both telomere shortening and repair of telomere damage, such as that encountered during oxidative stress, the normal loop structure at the end of telomeres is disrupted, exposing the 3′ overhang that under baseline conditions is “buried” in the loop structure.39,40 Exposure of the TTAGGG tandem repeat sequence then appears to activate p5341 and to stimulate responses known to include proliferative senescence and apoptosis.40,41 Thus, the intrinsic component of skin aging involves progressive oxidative stress and telomere signaling as telomeres shorten during serial cell division and in response to oxidative DNA damage.39
Telomeres normally exist in a loop configuration, held in place by the final 150–200 bases (TTAGGG repeats) on the 3′ strand that forms a single-stranded overhang. When the loop is disrupted when telomeres become critically short (e.g., after repeated cell divisions or when telomeres are damaged as a result of UV irradiation or oxidative damage), the overhang becomes exposed, activating the tumor suppressor protein p53 to induce proliferative senescence or apoptosis, depending on the cell type. IL = interleukin. (From Yaar M: Clinical and histological features of intrinsic versus extrinsic skin aging. In: Skin Aging. Springer, 2006, p. 9, with permission.)
Oxidative damage also affects cellular proteins, leading to the formation of multiple carbonyl groups (C = O). Such proteins are typically targeted for degradation by proteasomes whose function declines with age, leading to the accumulation of damaged proteins that interfere with proper cellular function.42
Another mechanism that plays a role in intrinsic aging is cellular senescence, the limited capacity of cells to divide. It is regarded by some as having evolved in multicellular organisms as a cancer-prevention mechanism.6 Senescent cells display critically short telomeres, irreversible growth arrest, resistance to apoptosis, and altered differentiation. They also overexpress genes that block progression into the cell cycle43–45 as well as genes encoding proteins such as fibronectin and proteases involved in modulation of extracellular matrix, such as collagenase and stromelysin. In addition, the levels of certain tissue inhibitors of MMPs are decreased.46
Additional mechanisms include amino acid racemization, a process that substitutes D-amino acids for L-amino acids within proteins, affecting protein function and rendering them less susceptible to degradation. Finally, nonenzymatic glycosylation of proteins occurs when reducing sugar aldehydes condense with protein amino groups, resulting in brown discoloration, loss of function, and altered degradation. Glycosylation of extracellular matrix proteins, such as dermal collagen, leads to cross-linking with trapping and sequestration of other unaffected proteins.
Many of the morphologic and functional age-associated changes in skin were documented many years ago47 and are not specifically referenced here. The most striking and consistent histologic change is flattening of the dermal–epidermal junction with effacement of both the dermal papillae and epidermal rete pegs.48 This results in a considerably smaller surface between the epidermis and dermis and presumably less communication and nutrient transfer. Dermal–epidermal separation has been demonstrated to occur more readily in old skin, undoubtedly explaining the propensity of the elderly to torn skin and superficial abrasions after minor trauma.
There is an age-associated epidermal thinning of 10%–50% between the ages of 30 years and 80 years.49 Variability in epidermal thickness and individual keratinocyte size increases, including those of the basal layer. Evidence suggests that epidermal keratinocytes senesce and senescent cells are more resistant to apoptosis. Therefore, such keratinocytes are more likely to accumulate mutations, increasing their risk for malignant transformation. Epidermal stem cells are a population of cells responsible for epidermal maintenance. It is unclear whether there is an age-associated decrease in epidermal stem cells. Some studies also show loss of epidermal stem cell population in aged skin as determined by the loss of cells expressing CD71 (transferrin receptor) and α6 integrin, accepted markers for keratinocyte stem cells,50 while others claim that unlike stem cells from other tissues, epidermal stem cells maintain their number and functionality with age and do not display ROS increases.51,52 The latter has been attributed to high levels of antioxidant enzymes particularly superoxide dismutase-1.53 At the electron microscopic level, sun-protected old skin is characterized by some widening of interkeratinocyte spaces, by reduplication of the lamina densa and anchoring fibril complex in the basement membrane zone, and by loss of the numerous microvillous projections of basal cell cytoplasm into the dermis.49
Average thickness and degree of compaction of the stratum corneum appear constant with increasing age, although individual corneocytes become larger. The skin surface pattern, a patchwork of fine lines possibly determined by papillary dermal architecture, reveals slight age-associated loss of regularity. There is an overall decreased lipid content in the stratum corneum of the elderly as well as decreased water content in part as a result of decrements in cholesterol synthesis.54 Age-associated increase in stratum corneum pH impedes lipid-processing enzyme activity.55 Age effects on percutaneous absorption depend in part on drug structure, with hydrophilic substances such as hydrocortisone and benzoic acid being less well absorbed through the skin of old versus young individuals but with hydrophobic substances such as testosterone and estradiol being equally well absorbed.56 Of perhaps greater clinical importance, aging markedly delays the recovery of barrier function in damaged stratum corneum, apparently because of slow replacement of neutral lipids, leading to decreased amount of lipids in the newly formed lamellar bodies.57 Lipid synthesis and activities of enzymes required to generate stratum corneum lipids decrease with age possibly because of aberrations in elements that regulate enzyme transcription, or abnormal autocrine/paracrine signaling.58
In the elderly, the skin often appears dry and flaky, especially over the lower extremities, an area in which a remarkable age-associated decrease in the content of epidermal filaggrin has been reported.59 Filaggrin, required for binding of keratin filaments into macrofibrils, is also decreased in the skin of patients with ichthyosis vulgaris, and its lack has been postulated to cause the increased scaliness in both conditions.59 Barrier function also may be affected by this structural change.
Epidermal turnover rate and thymidine-labeling index decrease approximately 30%–50% between the third and eighth decades, with a corresponding prolongation in stratum corneum replacement rate. Linear growth rates also decrease for hair and nails. Epidermal repair rate after wounding likewise declines with age.
A decrease in the number of enzymatically active melanocytes per unit surface area of the skin, approximately 10%–20% of the remaining cell population each decade, has been documented repeatedly, presumably reducing the body's protective barrier against UV radiation. Age-associated decline in DNA repair capacity compounds the loss of protective melanin and increases the risk for skin cancer development. The number of melanocytic nevi also decreases progressively with age, from a peak of 15 to 40 in the third and fourth decades to an average of four per person after age 50 years; such nevi are rarely observed in persons beyond age 80.
Between early and late adulthood there is a 20%–50% reduction in the number of morphologically identifiable epidermal Langerhans cells, the skin's immune effector cells responsible for antigen presentation. The remaining cells display morphologic abnormalities, including less and shorter dendrites, and they display reduced antigen-presenting capacity.60 These changes, compounded by decreases in cytokine production by keratinocytes and lymphocytes and failure of migration through the lymphatic system, presumably contribute to the observed age-associated decrease in cutaneous immune responsiveness.
An endocrine function of human epidermis that declines with age is vitamin D production.61 Vitamin D, by binding its nuclear receptor, induces the transcription of numerous genes.62 Vitamin D deficiency in adults leads to osteomalacia and low levels have been implicated in epidemiologic studies as contributing to diabetes, hypertension, and prevalent tumors.63 Aside from its well-studied role in calcium homeostasis, vitamin D, when bound to its nuclear receptor (1,25D-VDR) influenced transcription of numerous genes including those that encode proteins of the Wnt signaling pathway affecting the formation of the cornified epithelium as well as hair growth. 1,25D-VDR also activates genes that encode proteins that participate in the innate and adaptive immune responses and repress IL-17, a major inducer of autoimmune disorders such as type I diabetes mellitus, multiple sclerosis, lupus, and rheumatoid arthritis. 1,25D-VDR is also anti-inflammatory, as it decreases NFkB and COX2 activation. Finally, 1,25D-VDR induces the activity of the tumor suppressor p53 and p21 proteins and the activity of FoxO, preventing oxidative damage and inducing DNA repair enzymes in skin.64 Elderly individuals frequently have reduced serum levels of vitamin D. Although avoidance of dairy products (the principal dietary source of vitamin D), insufficient sun exposure, and sunscreen use undoubtedly contribute to vitamin D deficiency in the elderly, the level of epidermal 7-dehydrocholesterol per unit skin surface area also appears to decrease linearly by approximately 75% between early and late adulthood,61 suggesting that lack of its immediate biosynthetic precursor also may limit vitamin D production. Together these observations suggest that age-associated decrease in Vitamin D could accelerate the aging process and argue for use of vitamin D dietary supplements in the elderly.65
With regard to susceptibility to oxidative damage, there is progressive accumulation of damaged cellular proteins and lipids with aging.49,66 Furthermore, antioxidant defense systems decline with age, and, in addition, there is a decrease in DNA damage repair capacity.49 These changes in combination increase cellular mutability or their tendency to become senescent, or both.
Loss of dermal thickness approaches 20% in elderly individuals, although in sun-protected sites significant thinning occurs only after the eighth decade.67 Old dermis is relatively acellular and avascular, and there is age-related loss of normal elastic fibers and dermal collagen.68,69
Decreased inflammatory responses in the elderly are the result of decreased synthesis and secretion of keratinocyte-derived cytokines and inflammatory mediators in addition to decreased endothelial response. The dermal microvasculature in middle-aged or elderly subjects also may show mild vascular wall thickening, especially in the lower legs as a result of gravitational forces70; vascular wall thinning to less than one-half the normal young adult measurement, associated with absent or reduced perivascular veil cells, has been reported in skin of very elderly subjects and probably contributes to vascular fragility. Loss of elastin contributes to vascular rigidity. Electron microscopic studies show focal degeneration of the elastic component of dermal arterioles. The striking age-associated loss of vascular bed, especially of the vertical capillary loops that occupy the dermal papillae in young skin, and increased distance from the epidermis of existing loops, is thought to underlie many of the physiologic alterations in old skin, including pallor, decreased skin temperature, and the approximately 60% reductions in basal and peak induced cutaneous blood flow.71
VEGF of epidermal origin appears to play a major role in maintaining dermal vasculature, inducing the expression of antiapoptotic proteins in endothelial cells,70 and decreased VEGF level shown in aged mice and rabbits skin probably contributes to endothelial cells apoptosis.72,73 Also, evidence suggests that there is an age-associated decline of both angiogenic and antiangiogenic factors, disrupting cutaneous angiogenic homeostasis.74 Decreased endothelial cell permeability response and decreased capacity to induce white cell adhesion75 contribute to the compromised immune response. When exposed to intense heat or cold, aging vessels demonstrate reduced ability to constrict, dilate, or shunt.70 Compromised thermoregulation, which predisposes the elderly to sometimes fatal heat stroke or hypothermia, may be due in part to reduced vasoactivity of dermal arterioles and, in the latter instance, to loss of heat-conserving subcutaneous fat as well. Reduction in the vascular network surrounding hair bulbs and eccrine, apocrine, and sebaceous glands may contribute to their gradual atrophy and fibrosis with age.
Age-associated decreases in wheal resorption and dermal clearance of transepidermally absorbed materials have been reported,56 probably due to alterations in both the vascular bed and the extracellular matrix. Conversely, the time required for development of a tense blister after topical ammonium hydroxide application is nearly twice as long in older individuals, suggesting a decreased transudation rate with age in injured skin. Impaired transfer of cells as well as solutes between the extravascular and intravascular dermal compartments is suggested by several studies; multiple factors undoubtedly contribute.
With aging there is a decrease in the density and lumen size of lymphatic vessels accompanied by increased rigidity and decrements in lymphatic drainage, affected by decreased surrounding elastic fibers.70 The ability to effectively pump lymph from interstitial spaces into the lymphatics is impaired with aging in part because of decreased activity of enzymes that catalyze the production of nitric oxide.76
Biochemical changes in collagen, elastin, and dermal ground substance lead to increased skin rigidity primarily due to modifications in collagen. Collagen content per unit area of skin surface decreases approximately 1% per year throughout adult life,77 and the remaining collagen fibrils appear disorganized, more compact, and granular, and they display increased collagen cross-links.78–80 The latter is the result of decreased collagen I and III synthesis; decrements in enzymatic processing of collagen as well as nonenzymatic glycosylation, a process that leads to molecular damage of proteins with a long half-life such as collagen49; and increased collagenase levels. Such changes almost certainly contribute to impaired wound healing in the elderly.79
Beginning in early adulthood, elastic fibers decrease in number and diameter; by old age, they often appear fragmented, with small cysts and lacunae, especially near the dermal–epidermal junction81 most likely due to enzymatic degradation of elastin. Elastic fibers also show progressive cross-linkage and calcification with age. At the biochemical level, there is an age-associated decrease in numerous elastic fiber components, including elastin, fibrillin, and fibulin-2. With aging, the level of fibulin-5, an extracellular matrix protein that functions as a scaffold for elastic fibers, appears to decrease before other changes are observed, suggesting that loss of fibulin-5 is a marker for skin aging.82
The ground substance mucopolysaccharides, glycosaminoglycans (GAGs), and proteoglycans are decreased relative to dry weight or collagen content of the skin, especially hyaluronic acid,83 possibly due to decreased hyaluronan secretion or due to decreased hyaluronic acid extractability.84 Aging also affects GAG composition and binding to elastin, impeding the drainage of molecules into lymphatic vessels.70 These changes may adversely influence skin turgor because proteoglycans bind 1,000 times their own weight in water and also impact collagen fiber deposition, orientation, and size.85
Changes with age in the mechanical properties of the skin during adulthood include progressive loss of elastic recovery, consistent with gradual destruction of the dermal elastic network, and marked prolongation of the time required for excised skin to return to its original thickness. In vivo ultrasound studies also show age-associated differences in water distribution in the dermis,86 no doubt affecting dermal pliability, resilience, and elasticity. Overall, a picture emerges of aging dermis as an increasingly rigid, inelastic, and unresponsive tissue that is less capable of undergoing modifications in response to injury or stress.
Subcutaneous Tissue, Muscles, and Bone
Like other striated muscles, facial muscles show accumulation of the “age pigment” lipofuscin, a marker of cellular damage. Compounded by diminished neuromuscular control, this deterioration contributes to wrinkle formation.87 In addition, subcutaneous fat is depleted from distinct facial regions, including the forehead, preorbital, buccal, temporal, and perioral regions. In contrast, there is a prominent increase in fatty tissue in other areas, including the submental regions, the jowls, the nasolabial folds, and the lateral malar areas. In contrast to the young face in which fat is diffusely dispersed, fat in the aged face, subject to the force of gravity, contributes to sagging and drooping of the skin.88
Finally, like other parts of the skeleton, facial bones display reduced mass with age. Bone resorption affects particularly the mandible, maxilla, and frontal bones. Bone loss in these areas enhances the sagging of facial skin and contributes to the obliteration of the demarcation between the contour of the jaw and the neck that is so distinct in young adults.89
By the end of the fifth decade, approximately half the population has at least 50% gray (white) scalp hair, and virtually everyone has some degree of graying due to progressive and eventually total loss of melanocytes from the hair bulb.90 Loss of melanocytes is believed to occur more rapidly in hair than in skin because the cells proliferate and manufacture melanin at maximal rates during the anagen phase of the hair cycle, whereas epidermal melanocytes are comparatively inactive throughout their life span. More specifically, hair graying reflects loss of the melanocyte stem cell population in hair follicle bulge due, at least in part, to compromised interaction between two transcription factors, microphthalmia-associated transcription factor (Mitf) and Pax3 (see Chapter 72).91 Faulty migration of melanocyte stem cells into the bulb area of the hair92 has also been suggested to contribute. Additionally, high levels of H2O2 in the millimolar range have been reported in gray/white scalp.93 By oxidizing methionine, tryptophan, and cysteine residues on enzymes, H2O2 likely to interferes with the activity of tyrosinase as well as antioxidant enzymes by altering their tertiary structure and may thus affect melanogenesis in the human hair follicle.93
Scalp hair may gray more rapidly than other body hair because its anagen to telogen ratio (see Chapter 86) is considerably greater than that of other body hair. Advancing age is also accompanied by a modest decrease in number of hair follicles, due in part to atrophy and fibrosis. In addition, with aging there is an increase in the proportion of telogen hair follicles. Remaining hairs may be smaller in diameter and grow more slowly. One hypothesis suggests that melanocyte loss and lack of melanosomal transfer may increase oxidative stress level in highly metabolic hair follicle keratinocytes, affecting their function and viability.94
The process termed balding results primarily from the androgen-dependent conversion of the relatively dark, thick, terminal scalp hairs to lightly pigmented short, fine, vellus hairs similar to those on the ventral forearm. Women are affected less often and far less severely than men. However, in postmenopausal women, hair loss is also the result of decreased estrogen levels and estrogen to androgen ratio.95,96 Besides hair loss, almost 50% of women older than age 60 years display mild facial hirsutism, presumably attributable to the same hormonal changes as scalp hair loss. In susceptible women, testosterone and/or progestin derivatives that are present in some hormone replacement regimens may exacerbate these changes.
Cutaneous Glands and Nerves
Eccrine glands decrease by approximately 15% in average number during adulthood in most body sites. Spontaneous sweating is further reduced by more than 70% in healthy older subjects compared with younger controls, attributable primarily to a decreased output per gland, predisposing the elderly to heat stroke. Apocrine gland size and function also decrease with aging. Sebaceous gland size and number appear not to change with age, but there is an exponential decrease in sebum production in both men and women most likely due to a decrease in production of gonadal or adrenal androgens.97
Pacinian and Meissner's corpuscles, the cutaneous end organs responsible for pressure perception and light touch, progressively decrease to approximately one-third their initial average density between the second and ninth decades of life and display greater size variation and structural irregularities.
Decreased sensory perception in old skin encompasses optimal stimulus for light touch, vibratory sensation, and corneal sensation; ability to discriminate two points; and spatial acuity.98,99 Cutaneous pain threshold increases up to 20% with advancing adult age, and compromised arteriolar constriction on changing position from supine to standing is reflective of decreased responsiveness of the sympathetic nervous system.
Estrogens play a critical role in female development and reproduction and also influence skin and hair. Not surprisingly, their influence decreases dramatically after menopause. Menopause typically occurs in a woman's early 50s, so that, with life expectancy in the developed world approaching 80 years,100 women are postmenopausal for approximately one-third of their lives. In premenopausal women, the predominant estrogen is estradiol, which is produced by the ovaries,101 and after menopause levels decrease by more than 90%,102 with estron, a less active estrogen, becoming the predominant form.103 Progestin and androgen levels also fall markedly after menopause.103 The reduced levels of estrogen underlie many physiologic effects, including hot flashes, atrophy of reproductive tissue, and changes in nonreproductive tissues that are estrogen sensitive.103 Age-associated decrements in keratinocyte barrier function, immune-regulation, and wound healing appear to be compounded by decreased estrogen levels and/or decreased responsiveness of cells to existing estrogens. Because both estrogen and androgen receptors are expressed by skin-derived cells, both hormones are likely to play a role in skin structure and function.
Structural and Functional Changes in Postmenopausal Skin
Decreased circulatory levels of estrogens are associated with reduced dermal collagen content,104–106 increased cutaneous extensibility,107,108 and decreased elasticity.109 Also, decreased water-holding capacity, increased dryness, and increased fine wrinkling are reported after menopause,110 as are decreased sebum levels.111 These changes are related more to menopause than to chronologic age alone,112 and wrinkling is reported to be more pronounced in postmenopausal women who are not taking hormone replacement therapy than in treated women.113
After menopause, the decreased rate of wound healing is associated with reduced levels of collagen I.114 Estrogen and progesterone are also reported to modulate cutaneous inflammation, enhance keratinocyte proliferation and collagen synthesis, decrease the activity of MMPs, and increase the synthesis of dermal mucopolysaccharides and hyaluronic acid.96,115
Clinical and histologic features of actinically damaged skin are listed in Table 109-3. A prominent feature of photoaged skin is elastosis, a process characterized clinically by yellow discoloration and a sometimes pebbly surface (Fig. 109-2) and histologically by tangled masses of degraded elastic fibers that further deteriorate to form an amorphous mass composed of disorganized tropoelastin and fibrillin (eFig. 109-2.1A). Although fibrillin is abundant in the elastotic material deeper in the dermis, in the upper portions of the dermis at the dermal–epidermal junction, fibrillin is reduced.116 In addition, the amount of ground substance, largely composed of glycosaminoglycans (GAGs) and proteoglycans, increases in photodamaged skin, whereas the amount of collagen decreases, in part because of increased metalloproteinase activity. In contrast with aged sun-protected skin that demonstrates hypocellularity, photodamaged skin frequently displays an increased number of hyperplastic fibroblasts as well as increased inflammatory cells (eFig. 109-2.1B), including mast cells, histiocytes, and other mononuclear cells, giving rise to the term heliodermatitis (literally, “cutaneous inflammation due to sun”; Fig. 109-3). Immunohistologic studies show increased CD4+ T cells in the dermis. Dermal vasculature in mildly photodamaged skin displays venule wall thickening; in severely photodamaged skin, thin vessel walls with compromised perivascular veil cells display dilations (telangiectases).
Table 109-3 Features of Photoaged Skina ||Download (.pdf)
Table 109-3 Features of Photoaged Skina
Increased compaction of stratum corneum, increased thickness of granular cell layer, reduced epidermal thickness, reduced epidermal mucin content
Actinic keratoses (see Chapter 113)
Nuclear atypia, loss of orderly, progressive keratinocyte maturation; irregular epidermal hyperplasia and/or hypoplasia; occasional dermal inflammation
Reduced or increased number of hypertrophic, strongly DOPA-positive melanocytes
Lentigines (see eFig. 109-2.2)
Elongation of epidermal rete ridges; increase in number and melanization of melanocytes
Reduced number of atypical melanocytes
Diffuse irreversible hyperpigmentation (bronzing) (see eFig. 109-2.3)
Increased number of DOPA-positive melanocytes and increased melanin content per unit area and increased number of dermal melanophages
Fine surface lines
Deep furrows (see Figs. 109-2 and 109-3)
Contraction of septae in the subcutaneous fat
Stellate pseudoscars (see eFig. 109-2.4)
Absence of epidermal pigmentation, altered fragmented dermal collagen
Elastosis (fine nodularity and/or coarseness) (see Fig. 109-3)
Nodular aggregations of fibrous to amorphous material in the papillary dermis
Ectatic vessels often with atrophic walls
Ectatic vessels often with atrophic walls
Purpura (easy bruising)
Extravasated erythrocytes and increased perivascular inflammation
Comedones (maladie de Favre et Racouchot) (see eFig. 109-2.5)
Ectasia of the pilosebaceous follicular orifice
Concentric hyperplasia of sebaceous glands
Photoaged versus intrinsically aged skin of an elderly man. Habitually sun-exposed skin above the collar line is prominently wrinkled and lax, in contrast with the equally chronologically aged but sun-protected skin of the lower neck and shoulder. Despite the striking difference in appearance, both areas manifest age-associated functional decrements.
Photodamaged facial skin. A. Large masses of deranged elastic fibers characterize solar elastosis. A thin subepidermal grenz zone (asterisks) is present, and the epidermis is acanthotic. (Used with permission from Jag Bhawan.) B. Marked dermal inflammatory infiltrate associated with the heliodermatitis (dermatoheliosis) that is characteristic of ongoing and chronic actinic exposure. (Used with permission from Lorraine H. Kligman.)
Habitually sun-exposed skin of older fair-skinned persons is characteristically atrophic and irregularly pigmented. (From Halachmi S, Yaar M, Gilchrest BA: Advances in skin aging/photoaging: Theoretic and practical implications (Part I). Ann Dermatol Venereol 132:362, 2005.)
Photoaged skin may be permanently hyperpigmented or “bronzed” as displayed in this 54-year-old woman who remained darkly tanned throughout the year in areas exposed by her sunbathing attire during the summer. (From Yaar M, Gilchrest BA: Ageing and photoageing of keratinocytes and melanocytes. Clin Exp Dermatol 26:583, 2001, with permission.)
Depigmented pseudoscars. The dorsal forearm is a common site of these lesions, here interspersed with actinic purpura and other photoaging changes. (From Yaar M, Gilchrest BA: Ageing and photoageing of keratinocytes and melanocytes. Clin Exp Dermatol 26:583, 2001, with permission.)
Open comedones in the temporal region are called Favre–Racouchot disease.
Photoaging: heliodermatitis. Pronounced furrowing, yellow discoloration, and pebbly surface (solar elastosis) with plugged follicles on the neck. Arrows denote small actinic keratoses.
In contrast with chronologically aged skin, photodamaged epidermis is frequently acanthotic, although severe atrophy also can be seen in addition to loss of polarity and cellular atypia. Also, there is a more profound decrease in the number and function of Langerhans cells. Additional changes are described in Table 109-3.
The relative severity of sun-induced cutaneous changes varies considerably among individuals, undoubtedly reflecting inherent differences in vulnerability and repair capacity for the solar insult. Photoaging occurs not only in fair-skinned individuals (skin phototypes I and II) but also in individuals with darker skin phototypes III and IV with a history of ample past sun exposure. It usually involves the face, neck, or extensor surfaces of the upper extremities most severely. Interestingly, the gross appearance of photodamaged skin of individuals with skin phototypes I and II differs from that of individuals with darker skin types. The former generally show atrophic and dysplastic skin changes with actinic keratoses and epidermal malignancies, whereas the latter manifest hypertrophic responses such as furrowing, lentigines, and coarseness (eFig. 109-3.1).39 One study noted that patients presenting with basal cell carcinoma (BCC) are less wrinkled than peers of similar complexion and degree of photodamage,117 suggesting that certain phenotypes of photoaging correlate with a predisposition to mutation and carcinogenesis.
Photoaging. A. An individual with skin type I displaying atrophic skin photodamage response with relatively few wrinkles but with several actinic keratoses (arrows), and a site of previous basal cell carcinoma over the lateral aspect of the nose. B. An individual with skin phototype IV displaying hypertrophic skin photodamage response with deep wrinkles and leather-like coarse skin. (From Yaar M: The chronic effects of ultraviolet radiation on the skin: Photoaging. In: Principles and Practice of Photodermatology, edited by H Lim. New York, Taylor and Francis LLC, 2007, pp. 91-106, with permission.)
Photoaging is most apparent in whites but also occurs in Asians, Hispanics, and Africans. The differences in clinical appearance of photoaged skin between whites and other groups is primarily due to differences in their UV defense systems. In the latter three groups, melanin is a major form of protection, whereas in whites, melanin plays a lesser role, and stratum corneum thickening is relatively more important.118 One study reported a sun protection factor for black epidermis of 13.4, compared to 3.4 for white epidermis.119 Black epidermis transmitted approximately 6% of ultraviolet B (UVB) to the dermis, compared to almost 30% transmission through white epidermis.119 Similarly, only ∼18% of ultraviolet A (UVA) was transmitted into black dermis, compared to more than 55% to white dermis.119
Major clinical features of photoaging in Asian skin are solar lentigines and mottled pigmentation.120 Moderate-to-severe wrinkling occurs in Asians but only in the sixth decade and only in individuals who regularly spent ample time in the sun.121
There are no specific studies addressing photoaging in Hispanics, and studies on photoaging of black skin have been published only in African-Americans. As expected, fairer skinned Hispanics and Africans display clinical photoaging signs earlier and more prominently than those with very dark skin.98 Changes include fine wrinkling and mottled pigmentation.116,120
Mechanisms involved in intrinsic aging also play a role in photoaging.122 Additional mechanisms are discussed below.
Membrane and Nuclear Signaling
UV irradiation, in part through ROS generation that inhibits phosphatases whose function is to maintain receptors in their inactive state,123 activates (phosphorylates) cell surface receptors, including receptors for epidermal growth factor, IL-1, and TNF-α, to induce intracellular signaling culminating in activation of the nuclear transcription complex activator protein (AP)-1, composed of the proteins c-Jun and c-Fos.124 In intact human skin, even suberythemogenic doses of UVB [∼0.1 minimal erythema dose (MED)] transcriptionally upregulate and activate AP-1.125 Increased AP-1 activity interferes with synthesis of the major dermal collagens I and III by blocking the effect of transforming growth factor (TGF)-α, a cytokine that enhances collagen gene transcription.124,125 AP-1 also decreases the level of TGF-β receptors, further inhibiting collagen transcription,126 and also antagonizes intrinsic retinoid effects in skin, leading to a functional retinoid deficiency and reducing collagen synthesis normally promoted by retinoic acid bound to its nuclear receptors. Additionally, UV induces the synthesis and secretion of a cysteine-rich growth regulatory factor (CYR61) that reduces type I procollagen synthesis, increases MMP-1 levels, decreases TGF-β receptor level, and induces AP-1 activation.127 Hence, in habitually UV-irradiated photodamaged skin there is an overall reduction in collagen synthesis.128 Increased AP-1 activity also increases the levels and activity of several enzymes that degrade extracellular matrix components, notably the MMP-1 (collagenase), MMP-3 (stromelysin-1), and MMP-9 (92-kd gelatinase).77,124 UV also activates the nuclear factor κB transcription factor that induces the expression of multiple proteins as discussed in Section “Mechanisms of Intrinsic Skin Aging” 24 and aggravates the degradation of dermal matrix by increasing the levels of MMP-1 and MMP-9.125 Matrix degradation is further exacerbated by MMP-8 (collagenase) of neutrophil origin after neutrophil infiltration into UV-irradiated skin.129 Although there is also a concomitant upregulation of tissue inhibitors of metalloproteinases (TIMPs) that limit matrix degradation, TIMPs presumably are not completely effective in blocking cumulative damage to dermal collagen.130 UV also decreases FoxO mRNA level further compromising collagen I synthesis and increasing the transcription of MMP-1 and -2 (18C).
UV-induced collagen degradation is generally incomplete, leading to accumulation of partially degraded collagen fragments in the dermis, thus reducing the structural integrity of the skin.124 In addition, the large collagen degradation products inhibit new collagen synthesis,131 and, thus, collagen degradation itself negatively regulates new collagen synthesis. Interestingly, increased stress-associated AP-1 activity, increased CYR61 and MMP levels, and reduced collagen production have been documented in intrinsically aged skin,127,132 suggesting that similar mechanisms may contribute to chronologic aging, perhaps again through the generation of ROS, as discussed in Section “Mechanisms of Intrinsic Skin Aging.”
UV radiation, both directly and through generation of ROS induces the transcription of tropoelastin, a component of the mature elastic fibers.133 Fibulins 2 and 5 and fibrillin-1, components of the microfibrillar fraction of the dermal elastic fiber are also increased in the elastotic material.82 Furthermore, increased elastase levels are present in photodamaged skin as a result of elastase synthesis and secretion by neutrophils that are attracted to the area by inflammatory mediators.134 Thus, excessive unbalanced synthesis of elastic fiber components that undergo partial degradation results in the formation of amorphous elastotic material.
Mitochondria are cellular organelles that produce energy (adenosine triphosphate) by consuming oxygen. Although equipped with antioxidant defense systems, continuous generation of ROS damages mitochondrial DNA (mtDNA). To date, machinery to remove bulky DNA lesions has not been identified in mitochondria, although they display capacity for base excision repair relevant to repair of oxidative damage. Still, mtDNA mutation frequency is approximately 50-fold higher than that of nuclear DNA, and photodamaged skin has higher mtDNA mutation frequency than sun-protected skin, displaying large DNA deletions135–138 and resulting in decreased mitochondrial function, leading to further accumulation of ROS and compromising the cell's ability to generate energy. Also, a correlation was noted between decreased mitochondrial function and increased MMP-1 levels without concomitant increase of MMP-1-specific TIMP,136 exacerbating collagen degradation135–138 and aggravating skin photoaging.
Proteins are affected by oxidative damage, and photodamaged skin shows accumulation of oxidized, damaged proteins in the upper portions of the dermis.139 In vitro studies suggest that UVA is a major contributor and the accumulation of such proteins further inhibits proteasomal function and the ability of the cell to successfully degrade additional damaged proteins.140
In sun-exposed skin, the basement membrane becomes thicker and multilayered in part as a result of damage through MMP activation, affecting molecular transfer between the epidermis and the dermis and compromising epidermal health.141
The action spectrum for human photoaging has not been determined, but many studies have explored the relative contribution of the various spectral bands within sunlight, using animal models.
Despite the well-documented affects of UVB, UVA is suspected of playing a proportionately larger role in photoaging because of its minimally 10-fold greater abundance in terrestrial sunlight, far greater year-round and daylong average irradiance, and greater average depth of penetration into the dermis compared to UVB.
In rodent skin, an elastosis-like condition can be produced by prolonged intense irradiation with either a predominantly UVB or UVA source.142,143 UVB photons are on average 1,000 times more energetic than UVA photons and are overwhelmingly responsible for sunburn, suntanning, and photocarcinogenesis after sun exposure.144 UVB is the major cause of direct DNA damage and induces inflammation and immunosuppression, as well as synthesis and release of prostaglandins (PGs), particularly PGE2, through induction of the enzyme cyclooxygenase-2. UVB also induces ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines that stimulates cellular proliferation (contributing to cancer formation) and contributes to cutaneous angiogenesis by decreasing the expression of the angiogenic inhibitor thrombospondin-1 and inducing the expression of VEGF and platelet-derived endothelial cell growth factor, two angiogenic factors.145,146 UVB also triggers the penetration of elastase-producing leukocytes into the skin, aggravating elastin degradation.
Moreover, human skin exposed daily for only 1 month to suberythemogenic doses of UVA alone demonstrates epidermal hyperplasia, stratum corneum thickening, Langerhans cell depletion, and dermal inflammatory infiltrates with deposition of lysozyme on the elastic fibers.147 UVA also induces the synthesis and release of cytokines and MMPs, particularly collagenase (MMP-1) and elastase, and triggers mtDNA mutations.148–151 Both UVA and UVB lead to the generation of ROS that damage cellular lipids, proteins, and DNA.152,153 Studies using laser-capture microdissection of human skin show that p53-mutant keratinocytes of the basal layer, in addition to UVB signature mutations, have more mutations associated with UVA (and primarily 8-OXO-dG photolesions), suggesting that UVA is an important etiologic factor in the generation of BCC.42 UVA is more effective than UVB in inducing oxidative damage. Indeed, the degree of solar elastosis and cutaneous photoaging appear to correlate with the level of accumulated dermal protein oxidation139 but not epidermal oxidation, suggesting a superior antioxidant network and/or better repair capacity in the epidermis.
Sunlight also contains IR (760 nm to 1 mm).154 Wavelengths of 760–1,400 nm can penetrate the skin to reach the subcutaneous tissue without inducing a significant increase in skin temperature. In contrast, wavelengths of 1,400 nm to 1 mm are primarily absorbed in the epidermis and considerably increase skin temperature.155 IR is particularly important in regions of high insulation and aggravates UVA-induced dermal changes, producing severe elastosis. Even when delivered without UV, IR affects dermal elastic fibers and increases the amount of dermal ground substance.155 In the hairless mouse model, IR contributes to UV-induced thickening of the epidermis and dermis and alone induces the expression of MMP-3 and the mouse equivalent of MMP-1.154 Furthermore, in human skin, the expression of tropoelastin, a major component of elastic fiber that associates with microfibrils, is increased as a result of IR, and IR induces the expression of fibrillin-1, a component of the microfibrils.156 In addition, the level of MMP-12, the enzyme that degrades elastin, is increased.156 Thus, IR appears to contribute to UV-induced photoaging.
Many of the age-associated physiologic decrements, such as slowed wound healing and loss of immunoresponsiveness, also appear to be accelerated in sun-exposed skin. Furthermore, cells cultured from chronically sun-exposed skin sites differ from cells cultured from sun-protected sites of the same donors in having shortened culture life spans, slower growth rates, lower saturation densities, and altered responsiveness to retinoic acid,157 all changes also observed as a function of advanced chronologic donor age. Several of the mechanisms known to be involved in UV-mediated cellular damage are also postulated to underlie chronologic aging,158,159 although the changes only appear after the seventh decade.132 These include DNA injury and/or decreased DNA repair, oxidative damage, lysosomal disruption, elevated MMPs, reduced collagen production, and connective tissue damage.
Other Contributors to Extrinsic Aging
Cigarette smoking exacerbates photoaging, particularly in women, with a direct correlation between the number of pack-years smoked and the severity of wrinkling and grayish discoloration.160,161 Histologic analysis of “smoker's skin” reveals elastic fiber thickening and fragmentation, similar to that found in sun-damaged skin.162 However, whereas solar elastosis is restricted in the papillary dermis, elastic fiber changes in smoker's skin also occur in the reticular dermis. This dermal elastosis has been suggested to result from increased elastase activity in neutrophils,163 chronic dermal ischemia, and the pro-oxidant effects of cigarette smoke compounded by decreased levels of vitamin A, which reduce the capacity to quench free oxygen radicals and increase DNA damage.160,161 Smoking also has been associated with decreased stratum corneum water content160,161 and accelerated hydroxylation of estradiol, leading to decreased estrogens in the skin that may in turn contribute to dryness and atrophy.161 Smokers display poor wound healing capacity164 and increased incidence of skin cancers as well as increased severity of photoaging-like changes compared with nonsmokers who have otherwise similar risk factors,165 consistent with the possibility that mutagens present in cigarette smoke directly affect cells in the dermis and epidermis. By increasing oxidative stress, cigarette smoke impairs collagen synthesis and induces the synthesis and release of MMPs.166 Also, the polycyclic aromatic hydrocarbons that are present in cigarette smoke bind to the cytoplasmic aryl hydrocarbon receptor. When activated, the receptor translocates to the nucleus to induce the transcription of xenobiotic-metabolizing genes that encode ptoeins involved in growth control, cytokines, nuclear transcription factors and regulators of extracellular matrix proteolysis.166
Relevance to Skin Disease in the Elderly
Closely associated with aging is increased vulnerability to disease and injury. Disorders of the skin are known to be common and bothersome in the elderly, and some occur predominantly in this age group.1 Such disorders often appear to be the consequence of age-associated intrinsic losses of cutaneous cellular function. However, many dermatoses observed more commonly in the elderly reflect the higher prevalence of systemic diseases, such as diabetes, vascular insufficiency, and various neurologic syndromes, that compound physiologic changes in the skin itself. The increased prevalence of some disorders also may reflect reduced local skin care due to immobility or neurologic impairment rather than changes in the skin itself. As well, subtle age-associated changes in immune status may contribute, in analogy to the increased prevalence and severity of skin disease in patients with acquired immunodeficiency syndrome.
Reduced tolerance to systemically administered drugs is well documented in the elderly167 due to decrements in lean body mass, metabolism, and renal excretion of the active ingredients. Comparable data for topically applied medications do not exist, but it is tempting to postulate that retarded dermal clearance of absorbed material, reduced dermal mass and cellularity, and, possibly, altered metabolic capacity may render old skin more susceptible to both beneficial and adverse effects of topical medications or may at least alter the optimal therapeutic schedule. In the case of glucocorticoid preparations, relative vascular unresponsiveness may render blanching of erythema an unreliable indicator of other effects in old skin.
Selected common cutaneous disorders in the elderly are discussed briefly in the following sections, with special emphasis on their pathogenesis and clinical presentation in this population (Table 109-4). Most of these entities are covered more comprehensively in other chapters.
Table 109-4 Presumptive Pathophysiology of Common Cutaneous Disorders in the Elderly ||Download (.pdf)
Table 109-4 Presumptive Pathophysiology of Common Cutaneous Disorders in the Elderly
Focal epidermal homeostatic loss leading to increased endothelin-1
Squamous cell carcinoma and actinic keratosis
Ultraviolet-induced DNA damage
Basal cell carcinoma
Decreased DNA damage repair capacity
Cumulative age-associated DNA damage
Merkel cell carcinoma
Decreased DNA damage repair capacity; polyoma virus
Changes in patient's environment leading to Koebnerization
Disturbance of epidermal maturation (decreased filaggrin production and/or altered lipid profile)
Decreased water content in outer layers of stratum corneum Slower corneocyte transit
Penetration of irritants through damaged stratum corneum (?)
Altered sensory threshold (neuropathy) (?)
Adverse drug reaction
Compromised local cutaneous health predisposing to growth of infective organism
Age-associated decreased immune function
Underlying systemic disorder associated with decreased immune function
Impaired wound healing capacity (decreased levels of growth factors, decreased cellular proliferative capacity, increased perivascular fibrin deposition)
Underlying systemic disorder
Compromised local cutaneous health (venous stasis, arteriosclerosis, hypertension)
Flattening of the dermal-epidermal junction
Increased circulating autoantibodies
Medications with unsaturated ring structures
Impetigo and folliculitis in the elderly are usually caused by Staphylococci, in contrast to impetigo in the pediatric population, which usually is caused by Streptococci (see Chapter 176). Hence, in the older age group, impetigo should be treated with penicillinase-resistant semisynthetic penicillin or erythromycin until culture confirms the identity of the organism.194
Cellulitis is an infectious inflammatory process that involves the subcutaneous tissue and is caused most frequently by Streptococci or Staphylococci. Like other inflammatory conditions in the elderly, cellulitis may present with only subtle rubor, tumor, calor, and dolor. Predisposing factors with increased prevalence in the elderly include chronic edema, compromised circulation, diabetes mellitus, surgical sites, and asteatotic eczema.
Distinct forms of cellulitis (see Chapter 178) preferentially affect older individuals. These include orbital cellulitis that is caused by Streptococcus viridans alone or in combination with gram-negative bacteria. Another form of cellulitis that is relatively rare in the younger population is Pseudomonas cellulitis of the ear, an infectious process that affects elderly diabetic individuals. Erysipelas, a β-hemolytic streptococcal infection of the skin, is more common in the elderly and tends to spread more readily in this age group, creating a life-threatening situation.
Necrotizing fasciitis (see Chapter 179), caused by a strain of Streptococcus, is a rare cutaneous infection, but it is more frequent in the elderly and is associated with increased morbidity and mortality in this age group.
Methicillin-resistant Staphylococcus aureus (MRSA) has become an increasingly important pathogen in hospital and community acquired infections, and age >80 years is significantly associated with MRSA carriage.164 Because community-associated MRSA infection most often presents as skin and soft tissue infections, dermatologists should be aware of this possibility when managing infections in the elderly.
Scabies can occur in any age group, but nursing homes provide a fertile ground for rapid spread of the infestation. In the elderly, in part because of their decreased immunity, lesions may be atypical and display less inflammation and pruritus. In addition, the elderly frequently have xerosis, and their pruritus at times may be attributed to this etiology.
Dermatophytes and Yeasts196
Onychomycosis is present in approximately 40% of patients after age 60 years, and tinea pedis is present in approximately 80% of this patient population. Although usually present for decades, tinea pedis may exacerbate with age. Indeed, in elderly diabetic patients, interdigital tinea pedis may ulcerate and predispose to bacterial cellulitis, a presentation that is relatively rare in the young adult immunocompetent patient.
Cutaneous infections due to Candida albicans are common in the elderly. When recurrent or difficult to control, candidiasis may be a sign of poorly controlled diabetes, an endocrinopathy, malnutrition, or malignancy.
Viral (Varicella-Zoster Virus)163
The incidence of herpes zoster peaks at approximately 1,500 cases per 100,000 persons annually at age 75 years. Postherpetic neuralgia, uncommon in patients younger than 40 years old, occurs in more than 40% of patients aged 60–69 years and 50% of patients 70 years of age or older.100 A number of patients older than 60 years also experience paresthesias and muscle weakness. Decreased cellular immunity and impaired wound healing in the elderly may account for slower resolution of the acute eruption, but the pathogenesis of their postherpetic neuralgia is unclear. A new vaccine composed of live, attenuated varicella zoster virus is now available and reported to reduce the incidence of postherpetic neuralgia by 66.5%.197
Chronic ulcers of all etiologies are more common in the elderly than in younger individuals, presumably due to a combination of impaired wound healing and higher prevalence of underlying diseases. The most common are leg ulcers, usually in the setting of chronic venous insufficiency leading to venous hypertension (see Chapter 174). Exudation of macromolecules such as fibrinogen into the dermis may block the passage of oxygen and nutrients and sequester cytokines and growth factors required for tissue homeostasis, maintenance, and repair. The sclerotic indurated quality of affected skin, termed lipodermatosclerosis, is postulated to further impair healing. In addition, diseases such as diabetes mellitus and atherosclerotic peripheral vascular disease may contribute to ulcer evolution.
Decubitus ulcers (see Chapter 100) are proportionately far more common in elderly hospitalized patients than in younger patients, as the former tend to be less mobile, needing help turning in bed, and have additional aggravating disorders such as dry skin over bony prominences, incontinence, sensory deficiency, and/or poor nutritional state.199,200
Bullous pemphigoid is far more common after age 60 years than in younger persons, a predilection that may be explained in part by the age-associated increases in circulating autoantibodies and ease of dermal–epidermal separation,201 although many other autoimmune and blistering dermatoses are not more common in old age. Possibly, age-associated changes in the basement membrane itself render it specifically vulnerable to this disease process. Bullous pemphigoid is a self-limited condition that frequently resolves within 6–12 months, but elderly patients may experience increased morbidity and mortality because of debilitated general health or as a side effect of treatment.