Role of Age-Associated Alterations of the Dermal Extracellular Matrix Microenvironment in Human Skin Aging: A Mini-Review

Abstract

Human skin is largely composed of a collagen-rich connective tissue, which provides structural and functional support. The collagen-rich connective tissue is produced, organized, and maintained by dermal fibroblasts. During aging, dermal collagen fibrils undergo progressive loss and fragmentation, leading to thin and structurally weakened skin. Age-related alterations of collagen fibrils impairs skin structure and function and creates a tissue microenvironment that promotes age-related skin diseases, such as delayed wound healing and skin cancer development. This mini-review describes cellular mechanisms that give rise to self-perpetuating, collagen fibril fragmentation that creates an age-associated dermal microenvironment, which contributes to decline of human skin function.

Fig.1. Alterations of dermal connective tissue collagen are characteristic features of human skin aging

Nanoscale human skin dermal collagen fibrils were analyzed by atomic force microscopy (AFM). Representative AFM images of dermal collagen fibrils in young (25 years) and aged (84 years) sun-protected underarm skin. Bars=100nm. All procedures involving human subjects were conducted in accord with the regulations set forth by the University of Michigan Institutional Review Board, and all subjects provided written informed consent.

Fig. 2. Model for human skin connective tissue aging

Human skin is a primary target of ROS generated from both extrinsic and intrinsic sources, such as ultraviolet irradiation from the sun and metabolically-generated pro-oxidants. The passage of time and chronic exposure to ROS increases AP-1 complex, which in turn up-regulates CCN1 expression. Elevated CCN1 alters dermal fibroblast function leading to development of age-associated dermal microenvironment (AADM). AADM encompasses reduced production of collagens (thin skin dermis); 2) increased production of multiple MMPs (collagen fibril fragmentation); 3) and creation of a proinflammatory microenvironment (inflammaging), and thus AADM promotes skin connective tissue aging. AADM impairs dermal structural integrity and mechanical properties, and creates a tissue microenvironment that contributes to age-related decline of skin function, such as reduced strength and delayed wound healing, and promotes epithelial skin cancer.

Fig. 3. Wounding rapidly induces CCN1 in human skin in vivo

Partial thickness wounds were made in sun-protected buttock skin of healthy adult individuals by CO₂ laser. Skin samples were obtained at indicated times, and mRNA levels were quantified by real-time RT-PCR and normalized to mRNA internal control housekeeping 36B4. All procedures involving human subjects were conducted in accord with the regulations set forth by the University of Michigan Institutional Review Board, and all subjects provided written informed consent. Mean±SEM, N=6.