Regulation of senescence markers by the extracellular matrix and the mediating mechanisms of hyaluronan

Aging is a complex, multi-system, and multi-level dynamic biological process involving intricate crosstalk between cellular and tissue components. In 2025, Cell officially added the extracellular matrix (ECM) as a novel hallmark of aging, marking a pivotal shift in aging research from intracellular to extracellular regulatory networks. The ECM is a dynamic three-dimensional macromolecular scaffold composed of glycosaminoglycans (such as hyaluronan), collagens, elastin, proteoglycans, and glycoproteins, which not only provides structural support for tissues and organs but also serves as a core hub for micro-environmental signal integration and transduction. Its unique biological characteristics lie in two aspects: on one hand, it exhibits primary aging features, with its components and structural architecture undergoing progressive alterations with advancing age; on the other hand, it possesses integrated regulatory capability that can cross-systemically modulate intracellular and extracellular aging processes, thereby constructing a “structure-signal-function” cascade regulatory network that links traditional aging hallmarks. Among all ECM components, hyaluronan (HA), a core glycosaminoglycan, acts as an indispensable mediator in the ECM-mediated regulation of aging. Emerging studies have further confirmed that enhancing high-molecular-weight HA levels in vivo can effectively extend healthspan and reduce the risk of aging-related diseases such as cancer and chronic inflammation. Against this backdrop, this review aims to systematically elucidate the regulatory mechanisms of the ECM in four representative aging hallmarks, i.e., deregulated nutrient sensing, mitochondrial dysfunction, altered intercellular communication, and chronic inflammation. In terms of nutrient sensing regulation, the changes in modulates the activity of the mTORC1 signaling axis through integrin-mediated focal adhesion (FAs) assembly and mechanical transduction, where HA participates by interacting with its receptor CD44 to regulate the PI3K-AKT-mTORC1 pathway, thereby affecting cellular nutrient perception and metabolic homeostasis; moreover, abnormal HA accumulation under obese conditions can impair insulin sensitivity, further verifying its role in metabolic regulation. For mitochondrial dysfunction, change in mechanical properties (such as stiffness and acidification) and chemical composition of ECM can regulate mitochondrial fission, mitophagy, and reactive oxygen species (ROS) production, while HA degradation (driven by overexpressed degrading enzymes like TMEM2) generates low-molecular-weight fragments that activate the TGF-β-SMAD pathway to induce mitochondrial dysfunction, whereas high-molecular-weight HA exerts a protective effect by promoting mitophagy and restoring mitochondrial membrane potential and ATP levels. In the context of altered intercellular communication, the ECM regulates gap junction activity, mechanical signal transmission, and extracellular vesicle (EVs) secretion and transport; HA influences ECM stiffness to alter intercellular mechanical communication and directly binds to receptors such as CD44 to modulate cell-cell interactions, and it can also be packaged into EVs to participate in long-distance signal transduction. Regarding chronic inflammation, the ECM exerts a bidirectional regulatory effect: its degraded fragments act as inflammation amplifiers by activating Toll-like receptors (TLRs), while intact macromolecules (including high-molecular-weight HA) inhibit inflammatory responses; notably, the imbalance between HA synthesis and degradation is closely associated with the progression of chronic inflammation. Collectively, these findings comprehensively demonstrate that the ECM serves as an integrative regulator of aging by constructing a multi-dimensional regulatory network for aging hallmarks, and HA acts as the core mediator in this network. Based on these insights, this review proposes key directions for future aging research: first, to clarify the molecular mechanisms underlying the molecular weight-dependent functional switching of HA and its precise regulation via specific receptors and signaling pathways; second, to develop advanced tools (such as single-cell spatial omics and biomimetic mechanical scaffolds) for dynamically monitoring ECM-cell interactions during aging; third, to explore precise anti-aging strategies targeting HA, including regulating its synthesis and degradation, designing molecular weight-controllable HA derivatives, and combined targeting of downstream receptor pathways (e.g., CD44); fourth, to evaluate the potential of ECM-related indicators (especially HA and its metabolites) as biomarkers for early aging diagnosis and individualized anti-aging intervention efficacy assessment.