The Tripartite Regulatory Framework of the Skin Extracellular Microenvironment and Related Anti-aging Strategies

This review proposes a tripartite regulatory framework for the Skin Extracellular Microenvironment (SEM), which the authors conceptualize as three cross-talked functional domains: hydration, nutritional, and signaling microenvironments. It systematically elaborates on the core functional architectures of each component-for instance, Hyaluronic Acid (HA) as the foundational element of the hydration microenvironment, collagen-based transport pathways in the nutritional microenvironment, and multi-axis signal networks (inflammatory, biochemical, mechanical) in the signaling microenvironment. Based on this, age-related dynamic alterations within each domain were further delineated: the hydration microenvironment undergoes progressive HA degradation and reduced biosynthesis, leading to decreased skin water retention, increased transepidermal water loss, and clinical manifestations like dryness and fine lines; the nutritional microenvironment exhibits microvascular degeneration, disrupted nutrient transport, and advanced glycation end-product accumulation, impairing extracellular matrix metabolic homeostasis; the signaling microenvironment suffers from chronic inflammation, TGF-β/Smad pathway imbalance, and mechanical signaling dysfunction, triggering a cascade of "inflammatory activation-uncontrolled degradation- mechanical disruption." Cross-regulatory interactions among the three microenvironments (e.g., hydration-signaling coupling via TGF-β/HAS2) are summarized to highlight their integrated regulatory nature. Additionally, targeted anti-aging strategies are discussed: exogenous HA supplementation and endogenous activation for the hydration microenvironment, metabolic substrate supply (e.g., proline, trace elements) for the nutritional microenvironment, and multi-pathway modulation (e.g., anti-inflammatory agents, platelet-rich plasma, collagen stimulants) for the signaling microenvironment, with particular attention to the synergistic effects observed in combination approaches such as mesotherapy-based cocktails and exosome therapy. Overall, this framework integrates previously fragmented SEM research and provides a coherent theoretical basis for evidence-based clinical anti-aging strategies and future precision interventions targeting skin aging.