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      Vitamin A Antagonizes Decreased Cell Growth and Elevated Collagen-Degrading Matrix Metalloproteinases and Stimulates Collagen Accumulation in Naturally Aged Human Skin1

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          Abstract

          Damage to human skin due to ultraviolet light from the sun (photoaging) and damage occurring as a consequence of the passage of time (chronologic or natural aging) are considered to be distinct entities. Photoaging is caused in part by damage to skin connective tissue by increased elaboration of collagen-degrading matrix metalloproteinases, and by reduced collagen synthesis. As matrix metalloproteinase levels are known to rise in fibroblasts as a function of age, and as oxidant stress is believed to underlie changes associated with both photoaging and natural aging, we determined whether natural skin aging, like photoaging, gives rise to increased matrix metalloproteinases and reduced collagen synthesis. In addition, we determined whether topical vitamin A (retinol) could stimulate new collagen deposition in sun-protected aged skin, as it does in photoaged skin. Sun-protected skin samples were obtained from 72 individuals in four age groups: 18-29 y, 30-59 y, 60-79 y, and 80+ y. Histologic and cellular markers of connective tissue abnormalities were significantly elevated in the 60-79 y and 80+ y groups, compared with the two younger age groups. Increased matrix metalloproteinase levels and decreased collagen synthesis/expression were associated with this connective tissue damage. In a separate group of 53 individuals (80+ y of age), topical application of 1% vitamin A for 7 d increased fibroblast growth and collagen synthesis, and concomitantly reduced the levels of matrix-degrading matrix metalloproteinases. Our findings indicate that naturally aged, sun-protected skin and photoaged skin share important molecular features including connective tissue damage, elevated matrix metalloproteinase levels, and reduced collagen production. In addition, vitamin A treatment reduces matrix metalloproteinase expression and stimulates collagen synthesis in naturally aged, sun-protected skin, as it does in photoaged skin.

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          Most cited references42

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          Pathophysiology of premature skin aging induced by ultraviolet light.

          Long-term exposure to ultraviolet irradiation from sunlight causes premature skin aging (photoaging), characterized in part by wrinkles, altered pigmentation, and loss of skin tone. Photoaged skin displays prominent alterations in the collagenous extracellular matrix of connective tissue. We investigated the role of matrix-degrading metalloproteinases, a family of proteolytic enzymes, as mediators of collagen damage in photoaging. We studied 59 whites (33 men and 26 women, ranging in age from 21 to 58 years) with light-to-moderate skin pigmentation, none of whom had current or prior skin disease. Only some of the participants were included in each of the studies. We irradiated their buttock skin with fluorescent ultraviolet lights under standard conditions and obtained skin samples from irradiated and nonirradiated areas by keratome or punch biopsy. In some studies, tretinoin and its vehicle were applied to skin under occlusion 48 hours before ultraviolet irradiation. The expression of matrix metalloproteinases was determined by in situ hybridization, immunohistology, and in situ zymography. Irradiation-induced degradation of skin collagen was measured by radioimmunoassay of soluble cross-linked telopeptides. The protein level of tissue inhibitor of matrix metalloproteinases type 1 was determined by Western blot analysis. A single exposure to ultraviolet irradiation increased the expression of three matrix metalloproteinases -- collagenase, a 92-kd gelatinase, and stromelysin -- in skin connective tissue and outer skin layers, as compared with nonirradiated skin. The degradation of endogenous type I collagen fibrils was increased by 58 percent in irradiated skin, as compared with nonirradiated skin. Collagenase and gelatinase activity remained maximally elevated (4.4 and 2.3 times, respectively) for seven days with four exposures to ultraviolet irradiation, delivered at two-day intervals, as compared with base-line levels. Pretreatment of skin with tretinoin (all-trans-retinoic acid) inhibited the induction of matrix metalloproteinase proteins and activity (by 70 to 80 percent) in both connective tissue and outer layers of irradiated skin. Ultraviolet irradiation also induced tissue inhibitor of matrix metalloproteinases-1, which regulates the enzyme. Induction of the inhibitor was not affected by tretinoin. Multiple exposures to ultraviolet irradiation lead to sustained elevations of matrix metalloproteinases that degrade skin collagen and may contribute to photoaging. Treatment with topical tretinoin inhibits irradiation-induced matrix metalloproteinases but not their endogenous inhibitor.
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            Oxidative Stress, Caloric Restriction, and Aging

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              Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid)

              Topical tretinoin (retinoic acid) modifies fine wrinkles and certain other features of human skin damaged by exposure to the sun (photodamage), but histologic changes do not account for this improvement. In mice with photodamage induced by ultraviolet light, effacement of fine wrinkles by tretinoin is correlated with dermal collagen synthesis but not with histologic changes. We investigated whether collagen synthesis was reduced in photodamaged human skin and, if so, whether it could be restored by treatment with topical tretinoin. Biopsies of photodamaged skin from the extensor aspect of the forearm and skin from the buttocks, which had been protected from the sun, were performed on 26 healthy subjects. In addition, 29 patients with photodamaged skin were treated for 10 to 12 months with a daily application of 0.1 percent tretinoin cream (15 patients) or vehicle cream (14 patients). Skin-biopsy specimens obtained at base line and after treatment were assessed immunohistologically for evidence of dermal collagen I formation (collagen synthesis). Collagen I formation was 56 percent less in the papillary dermis of photodamaged skin than in skin protected from the sun (P < 0.001) and was correlated with the clinical severity of photodamage (r = -0.58, P = 0.002). Treatment of photodamaged skin with tretinoin produced an 80 percent increase in collagen I formation, as compared with a 14 percent decrease in collagen formation with the use of vehicle alone (P = 0.006). The formation of collagen I is significantly decreased in photodamaged human skin, and this process is partly restored by treatment with tretinoin.
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                Author and article information

                Journal
                Journal of Investigative Dermatology
                Journal of Investigative Dermatology
                Wiley
                0022202X
                March 2000
                March 2000
                : 114
                : 3
                : 480-486
                Article
                10.1046/j.1523-1747.2000.00902.x
                10692106
                e7a6aaa9-b050-4201-9d86-33c8c51f4398
                © 2000

                https://www.elsevier.com/tdm/userlicense/1.0/

                https://www.elsevier.com/open-access/userlicense/1.0/


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