Cutaneous Tissue Modifications with Aging
Age-related structural alterations in the skin have been well documented by histologic and ultrastructural examination of skin biopsy specimens from younger compared to older people . The fine, regular epidermal surface pattern changes to coarser and less regular ridges with aging. Epidermal projections into the dermis are retracted and the dermal-epidermal junction is flattened. The dermis becomes thinner, and there are fewer fibrillar collagen and elastic fibers in older skin. A progressive reduction with age in the dermis hyaluronic acid content has been also demonstrated, which could account for some of the most striking alterations of the aged skin, including decreased turgidity, altered elasticity, and less support for microvessels. Basic mechanisms underlying skin aging can be represented by a reduced cellular turnover and a prolonged time to recover after an injury . According to the majority of the experts in this field, the morphofunctional state of skin, to a large extent, depends on the state of microcirculation. As the skin
Table I Age-Associated Changes in Skin Microvasculature.
A. Skin microvascular remodeling
— Arteriolar wall hypertrophy
— Reduced capillary density ("capillary rarefaction")
— Venular dilation and congestion
B. Hemorheological changes
— Raised plasma fibrinogen
— Increased plasma viscosity
— Increased red-cell aggregability
— Decreased red-cell deformability
C. Skin perfusion Baseline perfusion
— Reduced capillary blood flow velocity
— Reduced blood flow through A-V anastomoses
— Reduced flow motion Stimulated perfusion
— Reduced hyperemic response to heat
— Reduced vasodilation during exercise
— Reduced sympathetic vasoconstriction to cold
— Reduced reactive hyperemic response to ischemia and pressure
— Reduced endothelium-dependent vasodilation nutrition is provided by the microvessels, an altered micro-circulatory function is thought to affect the trophic state of the skin. A number of age-associated functional and structural alterations are reported in the skin microcirculation and discussed in the following section (Table I).
With aging, density and size of blood vessels are reduced and, in particular, dermal papillary loops are significantly reduced in old skin compared with young skin, as described by Tenland and others since the early 1980s, and confirmed later on by Kelly and others. Skin capillary rarefaction has been recently reported by MacGregor and Serne in middle-aged patients with essential hypertension. The observation that the same abnormality is detectable in normotensive offspring of hypertensive subjects pointed out the hypothesis that skin capillary rarefaction, possibly dependent on a defective neoangionetic capacity, could represent a patho-physiologic mechanism underlying the development of high blood pressure [11, 12]. Whether or not a reduction in skin capillary density may contribute to the hypertension in the elderly is still unknown.
Capillaroscopic observations in old subjects documented a permanent dilatation and congestion of venules and capillaries in nailfold microvasculature (Figure 2), whereas other studies showed a decreased blood flow through AV anastomoses.
Besides remodeling of skin microvasculature, aging is associated with hemorheological changes, which, in turn, have negative influence on the microcirculation of various
Figure 2 Nailfold capillaroscopy from a 75-year-old man. Areas of focal capillary rarefaction are detectable (arrows). (see color insert)
tissues . In fact, a number of clinical observations show a rise of fibrinogen with advancing age, which contributes to a rise in plasma viscosity and red cells aggregation. Rheo-logical properties of red cells also change, resulting in a decreased cell deformability and sluggish blood flow. All these hemorheological changes affect blood flow in large vessels, but play an even more important role in the microcirculation, where the inertial forces, the corpuscular behavior of blood, and the aggregation phenomenon have a critical influence on blood flow dynamics. Although some observations show a relationship between the rise in blood viscosity with age and a decreased cerebral blood flow, there is no conclusive evidence about a negative influence of these age-dependent hemorheological changes on skin blood flow.
Age-Associated Changes in Skin Perfusion
Differences in skin perfusion between young and old people have been observed by various methods. More than 60 years ago, Brown and Roth showed a lower blood cell velocity in finger nailfold capillaries of old versus young subjects. These findings were confirmed subsequently by modern dynamic video microscopy: Quantitative capillary blood flow velocity measurement showed a significantly lower velocity in the toe and the finger nailfold of elderly compared to young subjects. However, this phenomenon was not demonstrated in other skin regions, such as the ventral surface of the forearm, where average capillary blood flow velocity was not significantly different between young and old subjects.
A marked heterogeneity of cutaneous microcirculation in resting conditions has been demonstrated by laser Doppler flowmetry, which allows continuous, noninvasive, real-time assessment of skin perfusion in a hemispheric illuminated tissue volume of 1 to 1.5 mL under a measuring probe . To understand the pathophysiologic meaning of the measurements, one must remember that the laser Doppler signal is generated by the movement of blood cells in both skin microvascular networks, that is, the subpapillary thermoreg-ulatory bed and the nutritive capillaries. Therefore this procedure yields information about nutritional and nonnutri-tional perfusion. Skin blood flow is significantly higher in the face than in the trunk and extremities, with the highest perfusion values detected at lip level, followed by the chin, forehead, and cheek. The lowest perfusion is found in the gluteal region: on the back of the foot and on the soles. Men exhibit a higher cutaneous perfusion than women, whereas age-related differences in skin perfusion at rest have not been demonstrated by most studies. In contrast, a significant age-related reduction in resting blood flow was observed at the dorsum of the hand and of the foot using a xenon-133 clearance method.
More evident are the differences in skin microcirculatory pefusion between young and old subjects when the responses to physiologic or pharmacologic stress are considered.
Skin microvasculature shows a decreased efficiency of vasodilator and vasoconstrictor adaptive responses to both neurally mediated and humoral stimuli. A reduced capacity of skin microcirculation in the elderly to adapt to a thermal stress is well demonstrated. Many recent studies have examined this aspect, and the overall results is that aging decreases the hyperemic response of cutaneous blood flow to direct heat. This lowered capacity is particularly evident during dynamic exercise. Other observations, however, suggest that the age-associated decline in heat loss during exercise may be masked by repeated exercise training, and that when the effects of chronic diseases and sedentary lifestyle keep physical activity to a minimum, heat tolerance appears to be minimally compromised by age. An inadequate vasodilation during exercise can hamper thermoregulatory capacity in hypertensive patients . On the other side, sympathetic vasoconstriction to cold appears to be reduced with aging, with a decreased capacity for thermoconservation, which may explain the intolerance to cold of which the elderly often complains.
The hyperemic response to prolonged pressure is another function of skin microcirculation that is blunted by aging. The cutaneous reactive hyperemic response to ischemia and pressure over the sacrum and the gluteal region has been found to be significantly reduced in geriatric patients compared to younger subjects. This could easily induce development of decubitus ulcers in the elderly during long periods of immobility.
Besides the capillary rarefaction and arteriolar wall hypertrophy responsible for the structural remodeling of skin microcirculation, defective functional mechanisms also contribute to an impaired capillary recruitment. A reduction of microcirculatory skin flow-motion in elderly people may play a role in the attenuated cutaneous vasoreactivity in response to heat and ischemic stress.
Endothelial senescence is supposed to represent a critical factor underlying microvascular aging. The molecular mechanism that could be mainly involved by aging is the activation of telomerase in human dermal microvascular endothelial cells, which controls their durability both in vitro and in vivo. Aging per se is associated with a mild impaired endothelium-dependent vasodilation of skeletal muscle resistance vessels, and brachial and coronary arteries. However, the study of endothelial function in the skin microvasculature demonstrated only a mild impairment of the endothelium-dependent vasoreactivity in elderly subjects with low risk profile of atherosclerosis . An aging-related decrease in the bioavailability of nitric oxide (NO), due to either reduced biosynthesis or increased breakdown triggered by enhanced oxidative stress, could account for this impairment. However, it is worth noting that, as suggested by studies of Noon and Khan, the skin microcirculatory response to acetylcholine (ACh) is mainly mediated by endothelium-derived prostanoids rather than NO, which is the mediator of ACh-induced vasodilation in brachial and coronary arteries. In fact, the skin response to ACh is 50 percent reduced by pretreatment with ASA (prostanoid synthesis inhibitor), whereas the forearm response to ACh is reduced by L-NMMA. By contrast, in older subjects a NO-dependent mechanism accounts for approximately 60 percent of the active skin vasodilation induced by hyperthermia, against the 20 percent representing the contribution of NO-dependent vasodilation in the skin of young subjects. This suggests that attenuated cutaneous vasodila-tion with age may be due to a reduction in, or decreased vascular responsiveness to, other mediators than NO.
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