THE EPIDERMIS

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.21 This is accompanied by a
more than 50 percent reduction in the number of these interdigitations per unit skin surface
length between the third and ninth decades. 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
following minor trauma such as bandage removal and to bulla formation in edematous sites. In
females a sharp decline in the number of interdigitations occurs between 40 and 60 years of age,
whereas in males the rate of decline is more constant throughout adulthood.22
Average interrete epidermal thickness probably remains constant with advancing age, but
variability in epidermal thickness and in individual keratinocyte size increases. 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.
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. 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.23 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.24 Subtle changes in overall stratum corneum lipid profile
with aging also may affect barrier function.22,25
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.26 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.26 Barrier function also may be affected by this
structural change.
Epidermal turnover rate and thymidine-labeling index decrease approximately 30 to 50 percent
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.
With increasing donor age, cultured keratinocytes and fibroblasts also show progressive decline
in the response to growth factors,27 associated with decrements in growth factor signal
transduction.28
A decrease in the number of enzymatically active melanocytes per unit surface area of the skin,
approximately 10 to 20 percent of the remaining cell population each decade, has been
documented repeatedly, presumably reducing the body's protective barrier against UV radiation.
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; such nevi are rarely
observed in persons beyond age 80.
Between early and late adulthood there is a 20 to 50 percent 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 shorter dendrites. These changes, compounded by decreases in production of
interleukin and perhaps other cytokines by keratinocytes, 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.29
Some elderly individuals also have reduced serum levels of vitamin D and/or osteomalacia,30
the decreased mineralization of bone classically associated with vitamin D deficiency. 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 percent between early and late adulthood,29 suggesting that lack of
its immediate biosynthetic precursor also may limit vitamin D production. Indeed, in one study,
older adult volunteers subjected to total-body UV irradiation produced far less vitamin D3 than
did complexion-matched younger adult volunteers exposed to the same UV dose.31
With regard to susceptibility to oxidative damage, there is no consensus about age-associated
changes in the activities of antioxidative enzymes, including catalase, superoxide dismutase,
glutathione peroxidase, or glutathione reductase.32,33

THE DERMIS
Loss of dermal thickness approaches 20 percent in elderly individuals, although in sun-protected
sites significant thinning
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occurs only after the eighth decade.34 Old skin is relatively acellular and avascular. Precise
histologic concomitants of wrinkling, if any, are unknown, although the age-related loss of
normal elastic fibers may be contributory, and increases in papillary dermal collagen are
observed in photoaged skin after medical or surgical treatment that improves wrinkling.35,36
Deep expression lines seem to result from contractions of connective tissue septa within the
subcutaneous fat.37
In one study, an approximately 50 percent reduction in mast cells and a 30 percent reduction in
venular cross sections were noted in the papillary dermis of buttock skin from elderly adults
compared with that from young adult controls, associated with a corresponding reduction in
histamine release and other manifestations of the inflammatory response following UV radiation
exposure. The dermal microvasculature in middle-aged or elderly subjects also may show mild
vascular wall thickening; vascular wall thinning to less than 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. Electron microscopic
studies show sporadic 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, is felt to underlie many of the physiologic alterations in old skin,
including palor, decreased skin temperature, and the approximately 60 percent reductions in
basal and peak induced cutaneous blood flow.38 Furthermore, 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,39 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.
Decreased vascular responsiveness in the skin of older individuals has been documented by
clinically assessing vasodilation and transudation after UV exposure and application of
standardized irritants, histamine, or the mast cell degranulating agent 48/80.39 However, factors
such as age-associated changes in percutaneous absorption or cytokine release also may
contribute to the response.39 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 subcutaneous fat as well.
Compared with young adult controls, healthy older subjects are less able to manifest skin
sensitivity to dinitrochlorobenzene or standard recall antigens, undoubtedly reflecting the well-
documented decrease in total number of circulating thymus-derived lymphocytes and in their
responsiveness to standard mitogens,40 as well as the above-mentioned local cutaneous changes.
Biochemical changes in collagen, elastin, and dermal ground substance during fetal and early
postnatal development are far greater than those described with advancing age, but collagen
content per unit area of skin surface decreases approximately 1 percent per year throughout adult
life,41 and the remaining collagen fibrils appear disorganized, more compact, and granular.42 In
rats, a gradual decline in collagen synthesis rate with advancing age was determined, and the rate
at 24 months was only 10 percent that at 1 month of age.41 In addition, approximately 50
percent of the newly synthesized collagen in old rats was degraded versus only 6 percent in
immature animals. Similarly, dermal fibroblasts derived from human donors of different ages
have an age-associated increase in basal and induced levels of interstitial collagenase mRNA due
to increased transcriptional activity of the collagenase promoter, as well as age-associated
decreases in concentrations of procollagen type I and type III, a measure of collagen synthesis
rate, in suction blister fluid. In women, both bone mass (due primarily to collagen I) and skin
collagen decline rapidly in the immediate postmenopausal years,43 suggesting an additional
influence of estrogen on collagen synthesis and degradation. Such changes almost certainly
contribute to impaired wound healing in the elderly.44 Finally, a number of biochemical
analyses indicate increased cross-linkage of the collagen molecule with advancing age.44,45
Beginning in early adulthood, elastic fibers decrease in number and diameter; by old age, they
often appear fragmented with small cysts and lacunae, especially in the dermal-epidermal
junction.46 Similar changes can be produced experimentally by incubation of dermal slices with
elastase or chymotrypsin in vitro, suggesting that enzymatic degradation of elastin may be a
mechanism for normal dermal aging. Elastic fibers also show progressive cross-linkage and
calcification with age in adult skin.
The few reports concerning the possible postmaturational changes in mucopolysaccharides
(glycosaminoglycans and proteoglycans) or other molecules of the ground substance in which
collagen and elastic fibers are embedded suggest decreases relative to dry weight or collagen
content of the skin, especially for hyaluronic acid,47 or in hyaluronic acid extractability48.
Electron-dense hyaluronic acid granules also decrease with age and in one study were not
detected in those over age 60.47 These changes may adversely influence skin turgor because
proteoglycans bind to 1000 times their own weight in water.
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 after
compression. In vivo studies of ventral forearm skin of 133 volunteers in each decade of life
revealed linear declines during adulthood of approximately 25 percent in both men and women
for elasticity and extensibility.49 Loss of elasticity began in childhood and continued through the
ninth decade, whereas extensibility was constant through the sixth decade and then declined
more rapidly thereafter.49
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 stress.

Hair Changes
By the end of the fifth decade, approximately half the population has at least 50 percent 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.50 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. Scalp hair may gray more rapidly than other
body hair because its anagen-to-telogen ratio 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.
The process termed balding results primarily from the androgen-dependent conversion of the
relatively dark, thick terminal scalp hairs to lightly pigmented short, fine vellous hairs similar to
those on the ventral forearm. Bitemporal hairline recession begins during late adolescence in
most women and virtually all men. The rate at which hair loss proceeds and its ultimate extent
are highly variable, with a strong hereditary predisposition for which the exact determinants are
unknown.51
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Assessment of baldness is hampered by lack of a precise definition, but by certain criteria,

advanced bitemporal and occipital hair loss in men increases in prevalence from 20 and 3
percent, respectively, at the end of the third decade to more than 60 and 25 percent by the
seventh decade. Women are affected less often and far less severely. However, estrogens prolong
the growth phase (anagen) of the hair cycle.51 In postmenopausal women, hair loss may be the
result of decreased estrogen levels, as well as a decrease in the estrogen-androgen ratio. It is
estimated that by age 50, more than 50 percent of women would have some degree of
alopecia,51 often diffuse rather than predominantly temporal and occipital as observed in men.
Whether this age-associated hair loss represents androgenetic alopecia or so-called senescent
alopecia,51 the association with decreased estrogen levels is impressive. Besides hair loss,
almost 50 percent of women over age 60 display facial hirsutism, presumably attributable to the
same hormonal changes as hair loss. In susceptible women, testosterone and/or progestin
derivatives that are present in some hormone-replacement regimens may exacerbate hair loss and
induce hirsutism.
Nerves and Cutaneous Glands
Eccrine glands decrease by approximately 15 percent in average number during adulthood in
most body sites. Spontaneous sweating in response to dry heat is further reduced, more than 70
percent in healthy older subjects as compared with younger controls, attributable primarily to a
decreased output per gland. Maximal sweat production has not been quantified in the elderly but
is almost certainly reduced and probably predisposes to heat stroke in this age group. Apocrine
gland size and function also decrease with aging. Lipofuscin (“age pigment―) gradually
accumulates with age in the secretory cells of both eccrine and apocrine glands.
Sebaceous gland size and number appear not to change with age. The exponential decrease in
sebum production of approximately 23 percent per decade beginning in the second decade in
both men and women (approximately 60 percent over the adult life span) is attributed to the
concomitant decrease in production of gonadal or adrenal androgens to which sebaceous glands
are exquisitely sensitive.52 The clinical effects of decreased sebum production, if any, are
unknown. There is no direct relationship to xerosis or seborrheic dermatitis.
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, as determined histochemically in two body sites,
and display greater size variation and structural irregularities. There are very few histologically
demonstrable aging changes in Merkel's disks or in free nerve endings.
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.53,54
Cutaneous pain threshold increases up to 20 percent with advancing adult age. The available data
do not permit differentiation among an age-associated increase in the prevalence of peripheral
neuropathy, a true aging change in healthy subjects, increased rate of heat dispersion in old skin
due to age-associated dermal alterations, an increased peripheral nerve threshold to painful
stimuli, and an increased central threshold to pain perception. The many psychological and social
factors influencing an individual's reaction to pain also may be presumed to vary with age. In any
case, either decreased awareness of or reaction to noxious stimuli facilitates wounding and
irritation of old skin.