Aging of the skin is not just a matter of appearance—it reflects deep cellular and molecular changes in the dermal tissue. Central to this process are alterations in the extracellular matrix (ECM) and the behavior of dermal fibroblasts, the primary cells responsible for producing and remodeling the ECM. While the decline in collagen, the most abundant dermal protein, is well-recognized as a hallmark of aging, the role of other ECM components, such as fibronectin, is less well understood.

Addressing this critical gap is a research team led by Yaelim Lee from Professor Rong Li’s laboratory at the Mechanobiology Institute, National University of Singapore.  Their study demonstrates that fibronectin—a crucial ECM protein that serves as a scaffold for other matrix proteins and supports cellular functions—decreases significantly in aged skin, providing new insights into the mechanisms underlying dermal aging.

The study used both mouse models and human cells and revealed that there was approximately 50% less fibronectin in aged mouse dermis compared to young skin. Similarly, human dermal fibroblasts (HDFs) isolated from elderly donors produced a much sparser and less organized fibronectin network in culture compared to those from young individuals. It was discovered that this reduction in fibronectin was not just because of slower cell growth; rather, it reflected a fundamental age-related impairment in the ability of fibroblasts to build and organize the fibronectin-rich ECM.

Immunofluorescence images showing loss of fibronectin networks in aHDFs compared to yHDFs.

A closer look revealed a strong link between this fibronectin deficiency and reduced levels of α5-integrin, a cell-surface receptor pivotal for assembling fibronectin fibrils outside the cell. While the gene expression of α5-integrin remained unchanged with age, the protein’s presence on the cell surface dropped markedly in aged fibroblasts. This suggests that the decline is due to posttranscriptional mechanisms rather than a dip in transcriptional downregulation.

To understand how this loss impacts fibroblast function, researchers reduced α5-integrin in young HDFs. These cells began to exhibit classic signs of cellular aging (senescence): they stopped dividing, their shape changed, and markers of cell proliferation diminished. Genome-wide profiling confirmed the activation of a senescence-related gene program. Thus, the loss of α5-integrin—and the resulting failure to assemble fibronectin ECM—appears sufficient to drive fibroblast aging.

Intriguingly, the study also found that providing these senescent-like cells with a structured ECM – in the form of cell-derived matrix (CDM) cultured from young HDFs – largely restored their ability to proliferate. However, simple coatings of soluble fibronectin were not enough; the three-dimensional, fibrillar organization of the ECM was key. This finding underscores the importance of intact ECM architecture for maintaining cell health and function.

The study highlights that age-related loss of α5-integrin and fibronectin ECM disrupts the supportive environment necessary for fibroblast vitality, promoting senescence and compromising skin integrity. These insights suggest that therapies aimed at preserving ECM structure, supporting integrin function, or mimicking youthful ECM environments could help maintain skin health and combat age-related dermal dysfunction. Further research into ECM components or properties that help restore cell growth when α5-integrin is lost may open new avenues for interventions in aging skin and related disorders.