Human Skin Aging and the Anti-Aging Properties of Retinol

Abstract

The skin is the most-extensive and -abundant tissue in the human body. Like many organs, as we age, human skin experiences gradual atrophy in both the epidermis and dermis. This can be primarily attributed to the diminishing population of epidermal stem cells and the reduction in collagen, which is the primary structural protein in the human body. The alterations occurring in the epidermis and dermis due to the aging process result in disruptions to the structure and functionality of the skin. This creates a microenvironment conducive to age-related skin conditions such as a compromised skin barrier, slowed wound healing, and the onset of skin cancer. This review emphasizes the recent molecular discoveries related to skin aging and evaluates preventive approaches, such as the use of topical retinoids. Topical retinoids have demonstrated promise in enhancing skin texture, diminishing fine lines, and augmenting the thickness of both the epidermal and dermal layers.

Keywords: MMPs; TGF-β; collagen; retinol; skin aging.

Figure 1

Human skin epidermal and dermal aging. Aging impacts human skin profoundly, with significant changes in its structure. Notable aspects of skin aging encompass the thinning of both the epidermis and dermis, as well as the graying of hair and reduced hair density. Epidermal aging is characterized by diminished expression of COL17A1 in the skin stem cell niche, affecting various components such as the interfollicular epidermis (IFE), melanocyte stem cells (McSCs), and hair follicle stem cells (HFSCs). This reduction weakens the attachment of stem cells to the basement membrane, ultimately contributing to epidermal aging. Meanwhile, dermal aging stems from dysfunction in dermal fibroblasts, including upregulation of CCN1, which drives elevated expression of MMPs, leading to collagen degradation, an increased presence of proinflammatory cytokines that foster an inflammatory microenvironment (referred to as “inflammaging”), and a reduction in collagen production by impairing TGF-β signaling.

Figure 2

Mouse models of dermal aging. Illustration outlining the establishment of mouse models simulating dermal aging through fibroblast-specific expression of (a) catalytically active human MMP1 (Col1a2;hMMP1) and (b) human CCN1 (h Col1a2;hCCN1) under the regulation of the fibroblast-specific Col-1a2 promoter and enhancer. The fibroblast-specific expression of hMMP1 or hCCN1 leads to the degradation of collagen fibrils, disrupting interactions between fibroblasts and collagen. This disruption results in diminished cell spreading and subsequent adaptive functional changes, contributing to the perpetuation of dermal collagen degradation through the induction of multiple MMPs. Additionally, it inhibits collagen synthesis by interfering with TGF-β signaling and promotes inflammaging by triggering the production of various age-related proinflammatory cytokines. Consequently, dermal aging creates a microenvironment conducive to the development of skin tumors.

Figure 3

Topical ROL exerts anti-aging effects in aged human skin. Topical ROL triggers changes in the epidermis and dermis, impacting key skin cell types: epidermal keratinocytes, dermal fibroblasts, and endothelial cells. It boosts epidermal thickness by activating IFE stem cells and promoting keratinocyte growth. ROL also enhances the dermal microenvironment by activating fibroblasts, fostering dermal blood vessel formation through endothelial cell proliferation. This occurs via the TGF-β/CTGF pathway, increasing mature collagen in aged skin. The improved vasculature from ROL enhances blood flow, benefiting keratinocyte growth and fibroblast activation. Keratinocyte proliferation might further stimulate VEGF, possibly aiding vessel growth. This interplay between keratinocytes, endothelial cells, and fibroblasts creates a reinforcing environment, potentially explaining ROL’s impactful anti-aging effects in aged skin. Skin sections embedded in OCT (7 μm thickness) were acquired from healthy buttock skin of aged individuals (with an average age of 76 ± 6 years), after a seven-day topical treatment with both a vehicle and 0.4% retinol. Skin sections were immunostained with Ki67 (upper, proliferation marker), CD31 (middle, endothelial cell marker), and Type I procollagen (lower, major collagen in the skin). Representative images of six individuals. Bar = 100 µm.