The AP2A1 protein has been found to be important for cell aging. When we decreased the amount of AP2A1, cells began to look younger and healthier. In addition, this protein helps organize structures within the cell called stress fibers, which are essential for cell adhesion and size. These results suggest that AP2A1 may be a good target for treatments that aim to rejuvenate cells and better understand how aging occurs.
Senescent cells are cells that have stopped dividing and functioning normally, usually as a result of aging or damage.
They increase in size and can release substances that affect the cells around them, contributing to health problems and age-related diseases.
Although they no longer multiply, these cells are still active and can negatively impact the health of tissues and organs.
The accumulation of senescent cells in various organs is a natural process that occurs with aging and is linked to the development of several age-related diseases. Among these diseases, neurodegenerative diseases stand out, such as Alzheimer's and Parkinson's, cardiovascular diseases, type 2 diabetes and cancer.
One type of cell that has been extensively studied in this context is human fibroblasts, which are cells that play an essential role in maintaining tissue structure.
These cells have a limited capacity for division. After a certain number of divisions, they enter a state known as "replicative senescence," where they stop dividing.
This phenomenon is caused by the shortening of telomeres, which are the ends of chromosomes. With each cell division, telomeres shorten, and this eventually leads to DNA damage.
When cells enter senescence, they undergo significant changes, such as increasing in size. These changes negatively affect their function, their ability to multiply, and the production of proteins essential to the cell.
In addition, senescent cells show an increase in the activity of an enzyme called β-galactosidase, which is associated with senescence, and they produce inhibitors that control the cell cycle, such as the proteins p53, p21, p16, and PAI-1.
Skin Fibroblast Cells
Although changes in cell shape are a common sign of senescence, the exact mechanisms that cause these changes are not yet well understood.
Another effect of senescence is the decreased ability of cells to move, which has implications for wound healing, as senescent cells can hinder this process.
The shape and ability of cells to move are linked to the state of stress fibers, which are internal structures of cells formed mainly by proteins such as actin and myosin.
These fibers play a key role in cell contraction and in the adhesion of cells to their extracellular matrix, which is a network of proteins that support cells. Changes in the organization and properties of these fibers affect several cellular processes, including adhesion, movement and mechanical sensitivity of cells.
In senescent cells, stress fibers have their organization altered, which can contribute to pathological problems, such as the development of cancer and other diseases.
Although the study of the proteins that make up stress fibers is still ongoing, our recent research has revealed that in human fibroblasts, these fibers are made up of at least 135 proteins, of which 63 are upregulated during replicative senescence.
Many of these proteins are related to the cytoskeleton, which is the structure that maintains cellular shape and organization.
A particular focus of this research, conducted by researchers at the University of Osaka, Japan, was on the protein AP2A1, which is part of a complex that helps form vesicles during a process called endocytosis.
This protein is important in the capture and transport of other proteins within the cell and has been linked to several diseases, but the details of its role in cellular senescence are not yet fully understood.
Increased expression of AP2A1 protein in senescent cells over the course of days. Immunostaining of endogenous AP2A1 (magenta) and actin filaments in stress fibers (phalloidin, green).
In these studies, they observed that the amount of AP2A1 in cells influences how they progress to senescence. When AP2A1 expression is reduced, cells show characteristics of rejuvenation, reversing some of the effects associated with senescence.
In addition, AP2A1 was also observed in cells exposed to UV radiation or drugs, suggesting that its role in senescence is not limited to fibroblasts.
They found that AP2A1 is localized together with another protein, integrin β1, along stress fibers. This association suggests that senescent cells maintain their large size and reinforce their adhesion to the substrate, which is important for their stability.
AP2A1 knockdown promotes cellular rejuvenation characteristics. Immunostaining of AP2A1 (magenta), actin filaments in stress fibers (phalloidin, green) and nuclei (Hoechst33342, blue) in 30-day senescent cells with si-control or si-AP2A1 (no AP2A1) transfection.
Thus, the research provides new insights into how stress fibers are altered during senescence and highlights AP2A1 as a potential biomarker and therapeutic target to promote cellular rejuvenation.
READ MORE:
AP2A1 modulates cell states between senescence and rejuvenation
Pirawan Chantachotikul, Shiyou Liu, Kana Furukawa, Shinji Deguchi
Cellular Signalling. Volume 127, March 2025, 111616
Abstract:
Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on the reorganization of actin stress fibers induced upon replicative senescence in human fibroblasts, widely used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers. Knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation, while its overexpression in young cells advanced senescence phenotypes. Similar functions of AP2A1 were identified in UV- or drug-induced senescence and were observed in epithelial cells as well. Furthermore, we found that AP2A1 is colocalized with integrin β1, and both proteins move linearly along stress fibers. With the observations that focal adhesions are enlarged in senescent cells and that this coincides with strengthened cell adhesion to the substrate, these results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.
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