New molecular mechanism involved in cellular senescence discovered: Expectations for rejuvenation through gene expression control

As our cells age, they enlarge and develop thicker stress fibers (cytoskeletal structures); however, the underlying mechanisms behind this have remained unclear. A research group led by Invited Researcher Pirawan Chantachotikul and Professor Shinji Deguchi of the Graduate School of Engineering Science at Osaka University, found that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) plays a key role in maintaining the structure of fibroblasts, which become enlarged during senescence. Moreover, they showed that AP2A1 is involved in senescence in epithelial cells. The findings may contribute to the development of anti-senescence agents and other technologies to delay senescence and extend healthy lifespan as well as treatments for aging-related diseases. The study was published in Cellular Signalling.

In this study, the researchers integrated molecular biology, imaging analysis, and engineering methods. They observed that AP2A1 was highly expressed along stress fibers in fibroblasts during senescence. Suppression of AP2A1 expression was shown to reverse traits characteristic of cellular senescence. They found that AP2A1 moved along stress fibers to supply integrin β1 to cell-matrix adhesion and thereby strengthen adhesion so that enlarged senescent cells can maintain their morphology. These findings indicate that AP2A1 expression control may contribute to the regulation of senescence and rejuvenation through the aforementioned mechanisms. In addition to replicative senescence, the AP2A1 expression was increased in ultraviolet- and drug-induced senescent cells (fibroblasts and epithelial cells). Furthermore, the results suggest that AP2A1 may serve as a marker of cellular senescence and a potential therapeutic target for aging-related diseases.

Deguchi said, "It has been empirically known that cells become larger and stress fibers (cytoskeleton) become thicker after continued culture (senescence), but the underlying mechanisms were unknown. In this study, we demonstrated that a molecule called AP2A1 is involved in the increases in cell size and stress fiber thickness. Our study is still ongoing and is producing further interesting results in terms of the regulation of senescence."

Journal Information
Publication: Cellular Signalling
Title: AP2A1 modulates cell states between senescence and rejuvenation
DOI: 10.1016/j.cellsig.2025.111616