Extending these findings to human tissues, researchers observed that fibrosis around breast implants was associated with upregulation of Notch and senescence pathways, suggesting ECM stiffness may create a cycle of fibrosis and tissue damage.

The authors emphasize that targeting ECM cross-links such as glucosepane could be vital in preventing stiffness-induced senescence and long-term tissue deterioration, opening new avenues for anti-aging therapies.

A groundbreaking preprint study has revealed that increased stiffness of the extracellular matrix (ECM) directly promotes cellular senescence, especially in vascular endothelial cells, marking a significant advance in aging research.

This ECM stiffening was found to elevate Notch signaling, which contributes to cellular senescence, and experiments showed that inhibiting Notch with the drug nirogacestat could mitigate these effects, pointing toward promising therapeutic strategies.

Using a hydrogel scaffold to isolate ECM stiffness, researchers demonstrated that as stiffness increased from soft to moderate or severe levels, blood vessel formation decreased while markers of senescence like p21, p16, and SA-β-gal rose significantly.

The study also identified a unique senescence-associated secretory phenotype (SASP) under mechanical stress, characterized by decreased cytokines IL-6, IL-8, and CXCL1, but increased IL-33, IL-1α, and IFN-γ, indicating a divergent pathway from typical senescent cells.