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Molecular Mechanisms of Cutaneous Aging: Connective Tissue Alterations in the Dermis

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Molecular Mechanisms of Cutaneous Aging: Connective Tissue Alterations in the Dermis Molecular Mechanisms of Cutaneous Aging: Connective Tissue Alterations in the Dermis Jouni Uitto and Eric F. Bernstein Departments of Dermatology and Cutaneous Biology. and Biochemistry and Molecular Phannacology. Jefferson Medical College. and Jefferson Institute of Molecular Medicine. Thomas Jefferson University. Philadelphia. Pennsylvania. U.S.A. Cutaneous aging is a complex biological phenomenon isms of innate versus extrinsic aging with emphasis on consisting of two distinct components, (a) the intrinsic, connective tissue alterations, primarily collagen and the genetically determined degenerative aging processes elastic fiber network. We also introduce a novel and (b) extrinsic aging due to exposure to the transgenic mouse model, expressing a human elastin environment, also known as "photoaging". These two promoter-reporter gene construct, suitable for studies on processes are superimposed in the sun-exposed areas biology and preventive pharmacology of the cutaneous of skin, with profound effects on the biology of cellular aging. Key words: photoaging/solar elastosis/ UV-irradiation/ and structural elements of the skin. This overview elastic .fibers/collagen. Journal of Investigative Dermatology summarizes our current understanding of the mechan- Symposium Proceedings 3:41-44, 1998 ne of the fastest growing segments of the patient matrix protein that accounts for about 80% of the dry weight of the populace seen in dennatology practice today are skin, provides tensile properties to the dermis, so as to allow skin to individuals seeking help for cutaneous aging, i.e., serve as a protective organ against external trautna (Uitto, 1990). The O sagging and wrinkling of the skin, the tell-tale signs elastic fibers, which account for 20/&-4% of the extracellular matrix in of youth spent on the beach, middle years on the sun-protected skin, form an interconnecting network that provides golf colltse. or just a visible reminder of the inescapable aging process elasticity and resilience to normal skin (Uitto, 1979). Finally, glycos­ (Vitto. 1997). The patients' complaints range from minor cosmetic aminoglycan/proteoglycan macromolecules, even though a minor problems to major disfigurement with profound psycho-social con­ component accounting fo r as litde as 0.1%-0.3% of the dty weight of sequences. Thus, cutaneous aging represents a spectrum of medical tissue, play a role in providing hydration to the skin, largely through conditions with severity ranging from mild wrinkling to the develop­ the water binding capacity hyaluronicof acid (Davidson, 1965). Thus, ment of premalignant and malignant lesions. processes that alter the relative proportions of these components, or Cutaneous aging is a complex biologic process affecting various degradative pathways that render these molecules nonfunctional, can layers of the skin, but the major changes are seen in the dermis. result in clinical manifestations recognized as part of the cutaneous Contributing to the complexity of cutaneous aging is the fact that aging process. there are two independent, clinically and biologically distinct, processes MECHANISMS OF INNATE AGING affecting the skin simultaneously. The flISt is innate or intrinsic aging, "the biologic clock," which affects skin in a manner similar to how it A variety of theories have been proposed to explain aging phenomena probably affects a variety of internal organs, i.e., by slow, irreversible in general, and some of them may be applicable to innate cutaneous tissue degeneration. The second process is extrinsic aging, or "photo­ aging as well. One of these theories relates to the Hayflick phenomenon aging," the result of exposure to outdoor elements, primarily ultraviolet that postulates that diploid cells, such as dermal fibroblasts, have a (UV) radiation (Gilchrest, 1995). The consequences of innate aging finite life-span in culture (Hayflick, 1979). This observation, when can be observed all over the skin, including sun-protected areas, extrapolated to the tissue level, coupled with depletion of the stem whereas in sun-exposed areas, particularly on the face and backs of cell population from the dermis, could be expected to result in cellular hands, photo damage is superimposed on the background of the ongoing senescence and degenerative changes in the dennis. innate aging process. Consequendy, the most noticeable changes on Another theory revolves around free radicals, suggesting that oxidat­ facial and neck skin, the prime focus of patient complaints, result from ive stress may damage not only lipid bilayers in cell membranes but a combination of intrinsic and extrinsic aging processes; however, it also connective tissue components of the dermis, particularly collagen has been suggested that as much as 80% of facial aging is attributable (Dalle Carbonare and Pathak, 1994). Other changes in innate aging to sun exposure (Gilchrest, 1989). process have been attributed to nonenzymatic glycosylation of proteins, Normal human dermis consists primarily of an extracellular matrix such as collagen. This theory has been put forward on the basis of ti of connective ssue, and three major extracellular components have observations in patients with poorly controlled hyperglycemia in been recognized to contribute to physiologic properties of the skin. diabetes mellitus, who present with premature aging signs, such as Specifically, fibers consisting of collagen, an abundant extracellular early cataracts and premature arteriosclerosis, due to nonenzymatic glucosylation of lens proteins and blood vessel collagens, respectively (Bucala and Cerami, 1992). Reprint requests to: Dr. Jouni Uitto, Department of Dermatology and Finally, cutaneous aging may be attributed to differential gene Cutaneous Biology, Jefferson Medical College, 233 S. 10th Street, Suite 450, expression. This theory implies that with advanced aging and senes­ Bluemle Life Sciences Building, Philadelphia, PA 19107-5541. cence, skin cells, such as dermal fibroblasts, alter their biosynthetic 1087-0024/98/$10.50 • Copyright © 1998 by The Society for Investigative Dermatology, Inc. 41 42 UITTO AND BERNSTEIN JID SYMPOSIUM PROCEEDINGS repertoire through differential gene expression. In relation to the exposure to UV irradiation of human skin is able to increase the extracellular matrixof connective tissue , it has been clearlydemonstrated activities of MMP, and elevated enzyme activities were shown to be that the rate of collagen biosynthesis is markedly lower in the skin of associated with significant degradation of collagen fibers consisting elderly than in fetal tissues or during the early postnatal years (Vitto primarily of type I collagen (Fisher et aI, 1997) . At the same time, UV et aI, 1989). The low level of collagen synthesis in the elderly individuals exposure was also shown to induce a specific tissue inhibitor of MMP may explain compromised wound healing. Furthermore , reduced repair (TIMP) (Fisher et ai, 1997). Thus, there appears to be a delicate balance capacity that will not be able to replenish collagen fibers removed by between the induction of the degradative enzymes and their inhibitors ongoing degradative processes, may lead to atrophy of the dermis. in photodamaged skin. Nevertheless, UV exposure appears to result in Similarly, the rate of elastin gene expression, as measured by mRNA a more degradative environment that results in loss of cutaneous steady-state levels in fibroblast cultures established from the skin of collagen. Loss of collagen with concomitant accumulation of poorly elderlyindividuals, is markedly reduced after the fourth or fifthe d cade functional elastotic material can result in a leathery, inelastic, and of life (Vitto et ai, 1989) . Again, this results in a situation where there yellowish appearance of skin, so-called cutis rhomboidalis nuchae, as is very little repair capacity to re-synthesize elastic fibers that are graphically illustrated in the neck area of an individual spending continually broken down by slow, yet steady, degradative processes. significant unprotected time outdoors. Collectively, the observations on dermal connective tissue com­ ponents in innate aging suggest an imbalance between the biosynthesis A TRANSGENIC MOVSE MODEL FOR PHOTOAGING and degradation, with less repair capacity on the tace of ongoing RESEARCH degradation. This imbalance will eventually lead to loss of collagen As indicated above, solar elastosis is the major alteration in photoaged and elastic fibers, manifesting clinically as atrophy and loss of recoil. skin with massive accumulation of elastotic material in the dermis. A number of in vivo models of cutaneous photoaging have been developed EFFECTS OF PHOTODAMAGE ON DERMAL CONNECTIVE to measure the amount of newly deposited elastic tissues after repeated TISSUE UV irradiation exposures. These models require administration of UV The histopathologic hallmark of photoaging is the massive accumulation radiation for relatively long periods of time, ranging from 3 mo to of so-called "elastotic" material in the upper and mid-dermis. This over 1 y (Kligman et aI, 1982, 1985; Bissett et ai, 1987, 1989; Kligman phenomenon, known as solar elastosis, has been attributed to changes and Sayre, 1991; Kochevar et aI, 1994). As with humans, animals in elastin, the major component of elastic fibers, primarily because the require a significant portion of their lifetime to acquire a significant accumulated material stains positively with elastin-specific histologic amount of solar elastotic material; however,
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