CD44 links matrix signals to nuclear control of aging and autophagy

Aging is often described as the accumulation of damage inside our cells, but a growing body of evidence suggests that a crucial part of the story takes place outside them, in the tangled web of proteins and sugars known as the extracellular matrix. A new review published in the journal Biogerontology argues that one molecule in particular, the cell surface receptor CD44, acts as a master translator between the aging matrix and the aging nucleus, converting changes in tissue architecture into the chronic inflammation, failing autophagy, and metabolic disruption that define growing old. The work, led by Syeda Ayesha Ali and colleagues at Henan University of Technology in Zhengzhou, China, synthesizes findings from vascular biology, neuroscience, immunology, and metabolic research into a single framework that could reshape how scientists think about interventions to extend human health span.

CD44 is far from an obscure protein. First identified decades ago as the principal cell surface receptor for hyaluronan, the large sugar molecule that gives many tissues their hydrated structure, CD44 rose to fame in cancer biology as a marker of tumor-initiating stem cells. Yet as the new review makes clear, the same structural features that make CD44 useful to tumors also make it a pivotal player in normal aging. The receptor is not a passive anchor. Through its extracellular domains, it binds hyaluronan, osteopontin, and other matrix components; through its cytoplasmic tail, it connects to the actin cytoskeleton,Src-family kinases, and an array of signaling complexes. Its gene can be spliced into dozens of different isoforms, each with distinct properties, and it can be cleaved by proteases to release fragments, including the intracellular domain known as CD44-ICD, that travel to the nucleus and alter gene expression. In effect, CD44 is a molecular switchboard with the ability to rewire a cell’s response to its surroundings.

The review’s central argument concerns how a remodeling extracellular matrix uses CD44 to drive what researchers call inflammaging, the low-grade chronic inflammation that accompanies aging. In young, healthy tissue, the matrix is rich in high-molecular-weight hyaluronan, a long-chain polymer that generally supports tissue integrity and even exerts protective effects. As tissues age, hyaluronan breaks down into shorter fragments, and the balance of matrix components shifts. These smaller fragments can engage CD44 together with innate immune receptors such as the toll-like receptors, activating the transcription factor NF-κB. NF-κB, in turn, switches on the production of pro-inflammatory cytokines and chemokines. The review emphasizes that this process is not uniform across the body. In vascular tissue, the release of fragmented hyaluronan drives a different arm of the response, the CD44-STAT3 axis, which suppresses autophagic flux and pushes endothelial cells into a senescent state. Senescent cells themselves secrete inflammatory signals, creating a feedback loop that sustains chronic inflammation long after the initial trigger has passed.

The mechanistic connection between CD44 and autophagy, the cellular recycling system, has emerged from recent work that the review highlights as foundational. A 2023 study in Nature Communications demonstrated that CD44 activation by hyaluronan fragments in vascular endothelium activates STAT3, which in turn suppresses the class III PI3K complex that is essential for initiating autophagy. The result is a decline in the cell’s ability to clear damaged proteins and organelles, a decline long recognized as one of the hallmarks of cellular aging. By placing CD44 upstream of this process, the review provides a coherent mechanistic explanation for why an aging matrix might directly cause a decline in cellular housekeeping, and it suggests that blocking CD44 signaling in the vasculature could preserve autophagy and delay endothelial senescence.

What makes the story more complex, and more intriguing, is that CD44’s effects are deeply context-dependent. The receptor is not a single entity but a family of isoforms generated by alternative splicing, and different tissues, and even different cells within the same tissue, express different combinations. In some settings, CD44 signaling promotes tissue repair and proteostasis. The naked mole-rat, a rodent famous for its exceptional longevity, produces very-high-molecular-mass hyaluronan that engages CD44 in ways that appear to enhance resistance to stress, and recent work has linked CD44 to enhanced activity of the ATF6 branch of the unfolded protein response, a key defense against endoplasmic reticulum stress. In other settings, such as kidney tubules under acute injury or liver fibrosis, CD44 signaling through NF-κB drives mitochondrial dysfunction and tissue scarring. The review argues that isoform switching and proteolytic processing determine which of these programs a cell enters, meaning that the same receptor can be a driver of degeneration or a support for regeneration depending on which version of the protein is on the surface and which fragments have been released into the cell.

New technologies are now revealing how precisely this dysregulation is patterned across the body. Single-cell RNA sequencing and spatial transcriptomics, which allow researchers to measure gene expression in individual cells while preserving information about their location, have shown that CD44 and its variant isoforms are not uniformly altered with age. Instead, specific cell populations within the vasculature, brain, adipose tissue, kidney, and liver show distinct patterns of CD44 upregulation or isoform switching. In the brain, astrocytes in aged tissue produce excess hyaluronan, potentially creating a matrix environment that limits neural stem cell function. In adipose tissue, genome-wide association studies have linked CD44 expression to type 2 diabetes, and anti-CD44 antibody treatment in obese mice has been shown to lower hyperglycemia and reduce inflammation in fat and liver. In kidney, CD44 expression in tubular cells has been tied to NF-κB p65-mediated mitochondrial dysfunction during acute injury. These findings suggest that targeting CD44 would need to be tissue-specific and stage-specific rather than a single global intervention.

The review also explores the possibility that CD44 acts as a mechanosensor, translating physical forces in the extracellular matrix into biochemical signals. Molecular dynamics simulations have revealed how the binding of hyaluronan to CD44 can be regulated by mechanical force, suggesting that the receptor may be one of the ways in which cells sense the stiffness and architecture of their surroundings. Because tissue stiffness changes with age, this places CD44 at the interface between the mechanical and biochemical dimensions of aging biology. It also connects the field to a broader realization, increasingly prominent in the literature, that the mechanical properties of the aging matrix are not merely a consequence of aging but an active driver of cellular behavior.

From a therapeutic standpoint, the review is cautiously optimistic. Because CD44 sits at the junction of matrix remodeling and intracellular signaling, it offers multiple points of intervention. Ligand competition, using soluble hyaluronan-binding molecules to prevent fragmented hyaluronan from engaging the receptor, could reduce inflammatory signaling. Antibody blockade, already tested in metabolic disease models, could modulate CD44 activity in specific tissues. γ-secretase modulation, which influences the release of the CD44-ICD nuclear fragment, could alter the receptor’s transcriptional effects. In tendinopathy, lentiviral gene therapy targeting CD44 has already been shown to reduce senescence-associated secretory phenotypes in experimental models. The review notes that the clinical translation of these strategies will require a much deeper understanding of when CD44 signaling is harmful and when it is protective, but the framework it presents suggests that such a distinction is now mechanistically tractable.

Perhaps the most significant contribution of the review is conceptual. By establishing CD44 as the mechanistic link between extracellular matrix remodeling and nuclear responses in aging, it provides a bridge between two fields that have largely developed in parallel. Those studying the hallmarks of aging have focused on intracellular processes such as genomic instability, mitochondrial dysfunction, and loss of proteostasis. Those studying the extracellular matrix have focused on fibrosis, stiffness, and matrix degradation. CD44 sits at the boundary, translating one into the other. If the framework holds up under further experimental scrutiny, it suggests that interventions aimed at preserving matrix quality, or at modulating how cells read the matrix, could have effects on aging that extend far beyond the tissue in which they are applied. In a field where the search for effective interventions to extend health span has often focused on cells themselves, the message of this review is that the ground in which those cells are embedded may be just as important a target.