Damage to cell membranes causes cell aging

Mechanical damage to the cell membrane was previously thought to trigger two simple cellular outcomes: regeneration or death. However, in this study, the researchers discovered a third result – cellular senescence.

“When I started this project, I just wanted to understand the mechanism of repair of damaged cell membranes,” recalls Prof. Keiko Kono, head of the Membranology Unit and senior author of the study, in which the unit’s Several members were involved, including Kojiro Soda, Yohsuke Moriyama, Noorhani Razali and co. “Unexpectedly, we discovered that damage to the cell membrane, in a sense, changes the fate of the cell.”

The key to determining cell fate is the extent of damage and the resulting influx of calcium ions. Damage to the thin cell membrane can be easily repaired, allowing cells to continue cell division without problems. Higher levels of cell membrane damage induce cell death. However, moderate levels of cell membrane damage convert cells to senescent cells after several days, although membrane resealing appears to be successful.

Cancer cells divide indefinitely. In contrast, normal non-cancerous cells have a limited capacity for cell division — about 50 times the first division ceases irreversibly, and the cells enter a state known as cellular senescence. Senescent cells are still metabolically active, but unlike young and healthy cells, they produce different secreted proteins that amplify immune responses in both nearby tissues and distant organs. These mechanisms can induce both beneficial and harmful changes in our bodies, including accelerated wound healing, cancer promotion, and aging. Over the past decade, several studies have shown that senescent cells are present in the bodies of animals, including humans, and that removing senescent cells restored body functions in experimental animals. can go. However, the cause of cell senescence in the human body remains a controversial topic. “Gene expression profiling and bioinformatics suggested that cell membrane damage defines the origin of senescent cells in our bodies, especially those close to damaged tissues,” explains Professor Kuno.

The best established trigger of cellular senescence is repeated cell division. Many other stresses also induce cellular senescence in the laboratory setting, such as DNA damage, oncogene activation, and epigenetic changes. A long-standing belief in the research field was that various stresses ultimately induce cellular senescence by activating the DNA damage response. However, the authors revealed that cell membrane damage induces cellular senescence through a different mechanism involving calcium ions and the tumor suppressor gene p53. These findings may help in developing strategies to achieve healthy longevity in the future.