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Recent research has discovered that physical harm to the cell’s outer layer can trigger aging at the cellular level in human cells.
The delicate membrane encasing our cells measures just 5 nanometers in thickness—merely 1/20th the width of a soap bubble. This membrane is susceptible to damage from everyday physiological activities, such as muscle movements and injuries to tissues. In response to this vulnerability, cells possess repair systems capable of mending membrane damage to some extent.
Mechanical damage to the cell membrane was previously believed to trigger two simple cellular outcomes: recovery or death. In this study, however, the researchers uncovered a third outcome – cellular senescence.
“When I started this project, I simply aimed to understand the repair mechanisms of the damaged cell membrane,” recalls Professor Keiko Kono, head of the Membranology unit and senior author of this study, which involved multiple members from the unit, including Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali, and colleagues. “Unexpectedly, we ended up discovering that cell membrane damage, in a sense, switches cell fate.”
Mechanisms of Cellular Fate Determination
The key to determining cell fate is the extent of damage and subsequent calcium ion influx. The thin cell membrane damage can be easily repaired, allowing the cells to continue cell division without any trouble. The highest level of cell membrane damage induces cell death. However, a middle level of cell membrane damage turns the cells into senescent cells several days later, even though membrane resealing seems successful.
Cancer cells divide unlimitedly. In contrast, non-cancerous normal cells have a limited capacity for cell division – around 50 times before division is irreversibly stopped, and the cells enter a state known as cellular senescence. Senescent cells are still metabolically active, but unlike young and healthy cells, they produce various secretory proteins that upregulate immune responses in both nearby tissues and distant organs. This mechanism can induce both beneficial and detrimental changes in our body, including acceleration of wound healing, cancer promotion, and aging. During the last decade, numerous studies have reported that senescent cells exist in animal bodies, including humans, and that the removal of senescent cells can rejuvenate body functions in experimental animals.
New Insights into Cellular Senescence
However, the cause of cell senescence in the human body remains a controversial topic. “The gene expression profile and bioinformatics suggested that cell membrane damage explains the origin of senescent cells in our bodies, specifically the ones near damaged tissues,” explains Professor Kono.
The best-established inducer of cellular senescence is repeated cell division. Many other stresses also induce cellular senescence in a laboratory setting, such as DOI: 10.1038/s43587-024-00575-6
Funding: Japan Advanced Plant Science Network, MEXT Japan, Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Ono Medical Research Foundation, Princess Takamatsu Cancer Research Fund, Relay For Japan Cancer Society, Naito Foundation.