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LE Magazine April 2004

Modulation of skin collagen metabolism in aged and photoaged human skin in vivo.
To the best of our knowledge, no study has been conducted to date to directly compare the collagen metabolism of photoaged and naturally aged human skin. In this study, we compared collagen synthesis, matrix metalloproteinase-1 levels, and gelatinase activity of sun-exposed and sun-protected skin of both young and old subjects. Using northern blot analysis, immunohistochemical stain, and Western blot analysis, we demonstrated that the levels of procollagen type I mRNA and protein in photoaged and naturally aged human skin in vivo are significantly lower than those of young skin. Furthermore, we demonstrated, by northern blot analysis, that the procollagen alpha1(I) mRNA expression of photoaged skin is much greater than that of sun-protected skin in the same individual. In situ hybridization and immunohistochemical stain were used to show that the expression of type I procollagen mRNA and protein in the fibroblasts of photoaged skin is greater than for naturally aged skin. In addition, it was found, by Western blot analysis using protein extracted from the dermal tissues, that the level of procollagen type I protein in photoaged skin is lower than that of naturally aged skin. The level of matrix metalloproteinase-1 protein and the activity of matrix metalloproteinase-2 were higher in the dermis of photoaged skin than in naturally aged skin. Our results suggest that the natural aging process decreases collagen synthesis and increases the expression of matrix metalloproteinases, whereas photoaging results in an increase of collagen synthesis and greater matrix metalloproteinase expression in human skin in vivo. Thus, the balance between collagen synthesis and degradation leading to collagen deficiency is different in photoaged and naturally aged skin.

J Invest Dermatol. 2001 Nov;117(5):1218-24

Mathematical models describing polymer dissolution: consequences for drug delivery.
Polymer dissolution is an important phenomenon in polymer science and engineering that has found applications in areas like microlithography, controlled drug delivery, and plastics recycling. This review focuses on the modeling efforts to understand the physics of the drug release process from dissolving polymers. A brief review of the experimentally observed dissolution behavior is presented, thus motivating the modeling of the mechanism of dissolution. The main modeling contributions have been classified into two broad approaches - phenomenological models and Fickian equations, and anomalous transport models and scaling law-based approaches. The underlying principles and the important features of each approach are discussed. Details of the important models and their corresponding predictions are provided. Experimental results seem to be qualitatively consistent with the present picture.

Adv Drug Deliv Rev . 2001 Jun 11;48(2-3):195-210

Enhanced skin permeation of a lipophilic drug using supersaturated formulations.
Supersaturation was used to enhance the permeation of a lipophilic model compound (a lavendustin derivative, LAP) through excised pig skin in vitro. The drug was dissolved in a series of liquid and semisolid vehicles (in which it had different solubilities) and which were prepared using either (i) the method of mixed cosolvents, (ii) the method of solvent evaporation, or (iii) the method of dissolving the drug with heating. Saturated formulations showed comparable permeation rates through the skin, independent of the absolute concentration of the drug in the vehicle. Supersaturated solutions at a degree of saturation of two resulted in a doubling of the drug permeation rate. These experiments show, therefore, that the percutaneous absorption of LAP may be consistently increased using supersaturated formulations, independent of the type and composition of the vehicles and independent of their method of preparation.

J Control Release. 2001 Jun 15;73(2-3):245-53

Image analysis of dermal collagen changes during skin aging.
OBJECTIVE: To determine progressive quantitative, directional and textural changes in dermal collagen as a function of age and sex and to estimate their evolutive trend with appropriate regression models. STUDY DESIGN: Ninety-six samples of abdominal skin from autopsy cases were analyzed. The ages ranged from 3.5 months to 86 years. Picro-Sirius-stained slides were examined by polarizing microscopy, and spatial density, directional features and texture of collagen were measured by computerized image analysis. Nonlinear regression models were built to estimate evolutive changes with respect to age. The relationship between spatial orientation of collagen bundles and age was best modeled by linear regression. RESULTS: The evolutive patterns of dermal thickness and spatial density of collagen bundles correspond to a second-order polynomial model with a progressive increase from childhood to middle age and a relatively sharp decrease after the seventh decade. The evolution of textural pattern of dermal collagen, defined by gradient analysis, depicts a sort of inverted U. Its complexity is maximum in the first year of life, decreases until the period 25-50 years and increases progressively after the sixth decade. The horizontal orientation of collagen bundles with intermingled fascicles oriented in other directions, shown by young individuals, is progressively simplified with aging. In elderly subjects, collagen bundles have a horizontal orientation. No significant sex-related differences were found. CONCLUSION: Dermal collagen changes related to aging are apparently independent of sex, at least in abdominal skin, and show characteristic curvilinear evolutive trends defined by decreased dermal thickness in the elderly, decrease in the spatial density of collagen bundles and increase in textural heterogeneity of the dermis. Progressive simplification in the orientation of collagen bundles leading to a predominant horizontal disposition followed a linear trend. These changes could contribute to providing a substantial morphologic basis to age-associated biomechanical alterations in the skin.

Anal Quant Cytol Histol . 1998 Dec;20(6):493-9

Aging of the extracellular matrix and its pathology.
Recent concepts on the mechanisms of aging of extracellular matrix (EM) are reviewed as well as its involvement in age-associated diseases. Cell differentiation, histogenesis and organogenesis can be analyzed in terms of the program of the biosynthesis of EM macromolecules during development, maturation and aging. The most important biological role of EM is the integration of cells in tissues, of tissues in organs and of organs in the whole organism. EM can directly influence cell behavior through the contact between EM and the genome mediated by structural glycoproteins (fibronectin, laminin, elastonectin, etc.) interacting with other EM macromolecules (collagen, proteoglycans, elastin) and the cytoskeleton by trans-membrane receptors (integrins). Most age-associated diseases exhibit a deviation (qualitative or quantitative) from the normal program of EM biosynthesis. Three examples are analyzed in some detail: atherosclerosis, diabetes and malignant tumors. The degradation of elastic fibers catalyzed by cellular elastase-type enzymes is observed in atherosclerosis and also in emphysema and skin aging. Several of these enzymes were isolated and characterized from platelets, fibroblasts, smooth muscle cells and lipoproteins. The biosynthesis of some of them increases with age and facilitates cell migration. Plasma fibronectin increases with age exponentially. This increase is absent or strongly attenuated in diabetes and some cancers. Tissue fibronectin increases in diabetes, Werner syndrome and in the peritumoral desmoplastic reaction while most tumor cells can no more retain fibronectin on their membrane facilitating their movement in the organism. These examples demonstrate the importance of the study of cell matrix interactions for gerontology.

Exp Gerontol. 1988;23(1):5-18

Fifty years of skin aging.
In developed countries, interest in cutaneous aging is in large part the result of a progressive, dramatic rise over the past century in the absolute number and the proportion of the population who are elderly (Smith et al, 2001). The psychosocial as well as physiologic effects of skin aging on older individuals have created a demand for better understanding of the process and particularly for effective interventions. Skin aging is a complex process determined by the genetic endowment of the individual as well as by environmental factors. The appearance of old skin and the clinical consequences of skin aging have been well known for centuries, but only in the past 50 y have mechanisms and mediators been systematically pursued. Still, within this relatively short time there has been tremendous progress, a progress greatly enhanced by basic gerontologic research employing immunologic, biochemical, and particularly molecular biologic approaches.

J Investig Dermatol Symp Proc . 2002 Dec;7(1):51-8

Physiological consequences of human skin aging.
The expression and treatment of cutaneous disease in the elderly differ from those applicable to younger adults. Anatomical changes in aging skin result in altered physiological behavior and susceptibility to disease. Decreased epidermal renewal and tissue repair accompany the aging process. The rate of hair and nail growth declines, as well as the quantity of eccrine, apocrine, and sebum secretion. There are alterations in immune surveillance and antigen presentation with aging. The cutaneous vascular supply is decreased, leading to decreases in inflammatory response, absorption, and cutaneous clearance. Impaired thermal regulation, tactile sensitivity, and pain perception occur as one ages. We summarize the major changes that occur during the intrinsic aging process of the skin to facilitate the recognition and treatment of skin disease in the older patient.

Cutis. 1989 May;43(5):431-6

Histologic changes in skin associated with aging.
This is a review of histologic changes noted in the skin of elderly individuals. Among the epidermal changes associated with skin aging are a flattened dermal-epidermal junction, giving the appearance of atrophy and cellular heterogeneity. The melanocyte density declines slowly, and the Langerhans cells decrease in number with advancing age. Among the dermal changes are attenuation in the number and diameter of elastic fibers in the papillary dermis, an increase in number and thickness of the same fibers in the reticular dermis, and a coarsening of collagen fibers with an increase in density of the collagen network. A decrease in the dermal cell population as well as a functional decline in glandular activity are also noted with intrinsic aging. A decline in hair number, rate of growth, and diameter, along with a slowing of the rate of growth of nails, have been well documented with progressive aging.

J Dermatol Surg Oncol . 1990 Oct;16(10):908-14

Aging and cross-linking of skin collagen.
This report represents a clear demonstration of a cross-link in collagen whose abundance is related to chronological aging of an organism. Recently its structure was identified as histidinohydroxylysinonorleucine. Quantification of the cross-link in various aged samples of bovine and human skin indicate that it rapidly increases from birth through maturation. Subsequently, a steady increase occurs with aging, approaching 1 mole/mole of collagen. This compound seems to be related to the relative proportions of soluble to insoluble collagen from skin in neutral salt, dilute acid, and denaturing aqueous solvents (higher concentration in the insoluble portion). It is absent from other major collagenous tissues such as dentin, bone and tendon.

Biochem Biophys Res Commun . 1988 Apr 29;152(2):898-903

Connective tissue biochemistry of the aging dermis. Age-associated alterations in collagen and elastin.
Cutaneous aging represents a complex situation in which at least two independent factors--innate aging and solar exposure--contribute to the development of degenerative changes in the dermis. The biochemical and ultrastructural evidence reviewed in this article indicates that reduced collagen deposition, as a result of diminished collagen biosynthesis and reduced proliferative capacity of the fibroblasts, could explain the development of dermal atrophy and would relate to poor wound healing in the elderly. At the same time, perturbations in the supramolecular organization of the elastic fiber network lead to alterations in the mechanical properties of the skin, as manifested by loose and sagging skin with reduced resilience and elasticity.

Clin Geriatr Med . 1989 Feb;5(1):127-47

Factors of skin ageing share common mechanisms.
Ageing has been defined as the accumulation of molecular modifications which manifest as macroscopic clinical changes. Human skin, unique among mammalians insofar as it is deprived of fur, is particularly sensitive to environmental stress. Major environmental factors have been recognized to induce modifications of the morphological and biophysical properties of the skin. Metabolites from ingested or inhaled substances do affect skin, which is also sensitive to endogenous hormone levels. Factors as diverse as ultraviolet radiation, atmospheric pollution, wounds, infections, traumatisms, anoxya, cigarette smoke, and hormonal status have a role in increasing the rate of accumulation of molecular modifications and have thus been termed 'factors of ageing'. All these factors share as a common feature, the capability to directly or indirectly induce one of the steps of the micro-inflammatory cycle, which includes the expression of ICAM-1 in endothelial cells. This triggers a process leading to the accumulation of damages in the skin resulting in skin ageing since ICAM-1 expression provokes recruitment and diapedesis of circulating immune cells, which digest the extracellular matrix (ECM) by secreting collagenases, myeloperoxidases and reactive oxygen species. The activation of these lytic processes provokes random damage to resident cells, which in turn secrete prostaglandines and leukotrienes. These signaling molecules induce the degranulation of resident mast cells which release the autacoid histamine and the cytokine TNF-alpha thus activating endothelial cells lining adjacent capillaries which release P-selectin and synthesize ICAM-1. This closes a self-maintained micro-inflammatory cycle, which results in the accumulation of ECM damage, i.e. skin aging. In this paper we review the evidence that two factors able to induce macroscopical and molecular modifications in the skin, protein glycation and stretch, activate the micro-inflammatory cycle. We further present evidence that three additional factors, two external factors (electromagnetic fields and psychological stressors) and one internal factor (neuropeptides) also activate the micro-inflammatory cycles and may therefore be considered as factors of skin ageing.

Biogerontology. 2001;2(4):219-29

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