Human skin, like all other organs, undergoes chronological aging. In addition, unlike other organs, skin is in direct contact with the environment and therefore undergoes aging as a consequence of environmental damage. The primary environmental factor that causes human skin aging is UV irradiation from the sun. This sun-induced skin aging (photoaging), like chronological aging, is a cumulative process. However, unlike chronological aging, which depends on the passage of time per se, photoaging depends primarily on the degree of sun exposure and skin pigment. Individuals who have outdoor lifestyles, live in sunny climates, and are lightly pigmented will experience the greatest degree of photoaging. During the last decade, substantial progress has been made in understanding cellular and molecular mechanisms that bring about chronological aging and photoaging. This emerging information reveals that chronological aging and photoaging share fundamental molecular pathways. These new insights regarding convergence of the molecular basis of chronological aging and photoaging provide exciting new opportunities for the development of new anti-aging therapies. This article reviews our current understanding and presents new data about the molecular pathways that mediate skin damage by UV irradiation and by the passage of time.
Model depicting solar UV irradiation damage to skin connective tissue. Ultraviolet irradiation (jagged arrows) activates growth factor and cytokine receptors on the surface of keratinocytes (KC) and fibroblasts (FB). Activated receptors stimulate signal transduction cascades that induce transcription factor AP-1, which stimulates transcription of matrix metalloproteinase (MMP) genes. In fibroblasts, AP-1 also inhibits procollagen gene expression. Matrix metalloproteinases are secreted from keratinocytes and fibroblasts and break down collagen and other proteins that comprise the dermal extracellular matrix. Imperfect repair of the dermal damage impairs the functional and structural integrity of the extracellular matrix. Repeated sun exposure causes accumulation of dermal damage that eventually results in characteristic wrinkling of photodamaged skin.
Ultraviolet irradiation stimulates generation of hydrogen peroxide (H2O2) in human keratinocytes. A, Time course for accumulation of H2O2 following UV irradiation from the UV-B/UV-A2 source of human keratinocytes. B, Time course of UV stimulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in human skin in vivo. Skin samples were obtained at the indicated times after UV irradiation (UV-B/UV-A2 source) and analyzed for NADPH oxidase activity. Results are mean ± SEM (error bars) of 5 experiments. ROS indicates reactive oxygen species; 2MED, twice the minimal erythema dose.
Ultraviolet irradiation activates intracellular kinases in human skin in vivo. Skin samples (A, No UV; B, UV) were obtained 4 hours after UV irradiation (twice the minimal erythema dose, UV-B/UV-A2 source) and analyzed for kinase (extracellular signal-related kinase [ERK] 1/2) activation by immunohistologic examination. The antibodies used specifically detect the activated, phosphorylated kinase. Results are representative of 5 subjects.
Ultraviolet irradiation causes degradation of collagen in human skin in vivo. Skin samples were obtained 24 hours after UV irradiation (twice the minimal erythema dose [2MED], UV-B/UV-A2 source). Insoluble, partially degraded collagen in the dermis was quantified. Results are mean ± SEM (error bars) from 6 subjects. SS indicates solar simulator.
A, Ultraviolet B/UV-A2 irradiation induction of matrix-degrading metalloproteinase-1 (MMP-1) and DNA damage are greater in light skin compared with dark skin. Human skin color value (L*) was determined by a color meter (Minolta CR200 Chroma Meter). L* is a measure of color value (lightness/darkness), and varies between 0 (dark) and 100 (light). Subjects with skin L* greater than 65 (light skin) were exposed to twice the minimal erythema dose of UV-B/UV-A2 (average exposure, 640 mJ/cm2 total UV irradiance). Subjects with L* less than 55 (dark skin) were exposed to 1280 mJ/cm2 total UV irradiance (equivalent to 4 times the minimal erythema dose for the light skinned group) and 2560 mJ/cm2 total UV irradiance (equivalent to 8 times minimal erythema dose for the light skinned group). Skin samples were obtained 24 hours after UV irradiation and analyzed for matrix MMP-1 messenger RNA (mRNA) levels by real-time reverse transcriptase polymerase chain reaction, and DNA thymine dimer photoproducts, by immunofluorescence. B, Thymine dimer immunofluorescence data are representative of 5 light skinned subjects exposed to twice the minimal erythema dose and 5 dark skin subjects exposed to 2560 mJ/cm2 (equivalent to 8 times the minimal erythema dose for light skinned group).
A, Ultraviolet A1 irradiation induction of matrix-degrading metalloproteinase-1 (MMP-1) and DNA damage are greater in light skin compared with dark skin. Human skin color value (L*) was determined as described in the legend to Figure 5. Subjects were exposed to the indicated doses of UV-A1, and skin samples were obtained 24 hours after UV irradiation. Matrix metalloproteinase-1 messenger RNA (mRNA) levels were quantified by real-time reverse transcriptase polymerase chain reaction, and DNA thymine dimer photoproducts were visualized by immunofluorescence. B, Thymine dimer immunofluorescence data are representative of 8 light skinned and 8 dark skinned subjects exposed to 110 J/cm2.
Collagen fibrils are damaged in photoaged and chronologically aged human skin. Transmission electron micrographs reveal that collagen fibrils (c) are fragmented and disorganized in photoaged and chronologically aged compared with sun-protected and young human skin. In sun-protected and young skin, intact collagen fibrils are observed as long strands (cut parallel) or circular arrays (cut perpendicular) in close proximity to fibroblasts (f). In photodamaged and aged skin, collagen fibrils are fragmented and replaced by amorphous material (a) surrounding fibroblasts. Sun-protected hip skin (A) and photodamaged forearm skin (B) were obtained from a 67-year-old subject; young skin (C) was from the hip of a 25-year-old subject; and aged skin (D) was from the hip of an 83-year-old subject.
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