Natural and sun-induced aging of human skin

Abstract

With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases.

Figure 1.

Morphological alterations of collagen and elastin fibers in aged human skin. Collagen second harmonic generation (SHG) (blue, total SHG signal, backward + forward, λ_exc= 820 nm) and elastin autofluorescence (green, λ_det = 500–550 nm) of sun-exposed forearm skin samples from individuals aged 25 (top left) and 54 (top right) years, and sun-protected buttocks skin samples from individuals aged 25 (lower left) and 83 (lower right) years. Shown are maximum projections (15-µm thickness). SHG imaging highlights abundant collagen fibers in young skin (top and bottom left), and relatively reduced mature collagen content and increased fragmentation in photoaged (top right) and aged skin (bottom right). In addition, photoaging and chronological aging are characterized by the disappearance of small elastin fibers in the upper dermis. Photoaging is characterized by accumulation of elastotic material composed of aggregated elastin fibers (top right). (Human study guidelines approved by the University of Michigan Institutional Review Board.)

Figure 2.

ROS-mediated activation of RTKs signaling cascades by UV irradiation. (Upper panel) In absence of UV irradiation (basal conditions), RTKs and downstream signaling in skin cells are maintained in a low state of activation by protein tyrosine phosphatase activities that dynamically dephosphorylate RTKs. These conditions favor normal collagen synthesis and low production of matrix metalloproteinases (MMPs). (Lower panel) Absorption of UV irradiation energy by skin cell components, in the presence of molecular oxygen, generates reactive oxygen species (ROS) that react with cysteine in the catalytic site of protein tyrosine phosphatases. Inhibition of protein tyrosine phosphatases by reaction with ROS increases net RTK phosphorylation levels and triggers downstream signaling cascades that include mitogen-activated protein kinase (MAPK) phosphorylation and activation of activator protein-1 (AP-1) transcription factor. Activated AP-1 represses collagen production and increases MMP gene transcription. As a result, UV irradiation induces transient collagen deficit.

Figure 3.

Accumulation of fragmented collagen in the dermal extracellular matrix leads to sustained reduction of collagen production in chronologically aged and photoaged human skin. (Left panel) In young skin, intact collagen within the dermal extracellular matrix provides attachment sites and mechanical resistance for fibroblasts. Fibroblasts are able to stretch and, under relatively high mechanical tension, show normal collagen homeostasis (collagen production is high, MMP production is low). (Middle panel) On exposure to UV irradiation (photoaging) or oxidative stress (chronological aging), elevated ROS activate signaling cascades that promote reduced collagen synthesis and increased MMP production. Active MMPs cleave the collagenous extracellular matrix, whereas reduced procollagen production limits repair. (Right panel) Accumulation of collagen fragments, which occurs with chronic UV exposure and the passage of time, impairs the mechanical and functional properties of the dermal extracellular matrix. Fibroblasts respond to this degraded dermal extracellular microenvironment by up-regulating MMP expression and down-regulating collagen production, thereby creating a self-sustaining phenotype that promotes skin fragility and age-related diseases.