Damage To Cell Membranes Causes Cell Aging

Our cells are surrounded by a delicate membrane that can be easily damaged by physiological activities like muscle contraction and tissue injury, and our cells are equipped with mechanisms that can repair membrane damage to a certain degree. Previously mechanical damage to the cell membrane was believed to trigger 2 outcomes, either recovery or death. This study revealed a third outcome: cellular senescence.

"When I started this project, I simply aimed to understand the repair mechanisms of 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."

The extent of damage and subsequent calcium ion flux are the key to determining a cell’s fate. The best scenario is that with minor damage the thin cell membrane can easily be repaired allowing the cell to continue cell division without trouble. On the other hand, major damage to the cell membrane can’t be repaired, inducing cell death. But middle levels of damage to the cell membrane can turn cells into senescent cells several days later, even if resealing the membrane seems successful. 

Unlike cancerous cells, non-cancerous normal cells have a limited capacity for cell division. This is around 50 times before division is irreversibly stopped when the cells can enter a state called cellular senescence.  Senescent cells are still metabolically active, but unlike healthy cells they secrete various proteins that upregulate immune responses in surrounding tissues and organs, earning the nickname of zombie cells. This mechanism can be both beneficial and detrimental ranging from accelerated wound healing to cancer promotion and aging. The cause of cell senescence has been the subject of many studies and remains a controversial subject.

"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.

According to the researchers, while many stressors induce cellular senescence in lab settings such as DNA damage, oncogene activation, and epigenetic changes, thus far the best-established inducer is repeated cell division. Long-standing dogma was that various stresses induce cellular senescence ultimately via activation of DNA damage response. This research revealed that cell membrane damage induces cellular senescence via a different mechanism that involves calcium ions and the tumor suppressor gene p53.