It has been found through recent research that aging at the cellular level in humans can be triggered by physical harm to the cell’s outer layer.

The membrane that encases our cells is incredibly fragile, measuring just 5 nanometers in thickness, which is only 1/20th the size of a soap bubble. This membrane is prone to damage from everyday activities like muscle movements and injuries to tissues. To combat this, cells have repair systems that can help to some extent in repairing membrane damage.

Previously, it was believed that mechanical damage to the cell membrane resulted in only two outcomes: recovery or death. However, this study has revealed 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

Determining cell fate is dependent on the extent of damage and calcium ion influx that follows. If the damage to the thin cell membrane is minor, the cells can quickly repair themselves, resulting in a seamless continuation of cell division. However, severe damage to the cell membrane leads to cell death, while moderate damage transforms the cells into senescent cells days later, despite successful membrane resealing.

Normal non-cancerous cells can divide a limited number of times, approximately 50, before reaching a state of cellular senescence, in which further division is no longer possible. Senescent cells are still active metabolically, but they produce a range of secretory proteins that upregulate immune responses in both nearby tissues and distant organs. Such a mechanism can lead to beneficial or harmful changes in our body, such as promoting cancer, accelerating wound healing, or aging. Researchers have discovered that senescent cells exist in humans and other animals, and removing them can rejuvenate body functions in experimental animals.

New Insights into Cellular Senescence

Despite extensive research, the cause of cellular senescence in our body remains a subject of debate. Professor Kono explains that gene expression profiling and bioinformatics studies suggest that senescent cells near damaged tissues originate from cell membrane damage. Repeated cell division is the most common inducer of cellular senescence, but other factors, such as DNA damage, oncogene activation, and epigenetic changes, can also trigger it. Previously, it was assumed that various stresses induce cellular senescence by activating the DNA damage response. However, the authors of the study found that cell membrane damage initiates cellular senescence via a different mechanism involving calcium ions and the tumor suppressor gene p53. These findings could pave the way for developing strategies to achieve healthy longevity in the future.

This news is a creative derivative product from articles published in famous peer-reviewed journals and Govt reports:

1. Suda, K., Moriyama, Y., Razali, N. et al. Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts. Nat Aging (2024).
2. Andrews, N. W., Almeida, P. E. & Corrotte, M. Damage control: cellular mechanisms of plasma membrane repair. Trends Cell Biol. 24, 734–742 (2014).
3. McNeil, P. L. & Steinhardt, R. A. Plasma membrane disruption: repair, prevention, adaptation. Annu. Rev. Cell Dev. Biol. 19, 697–731 (2003).
4. Sonnemann, K. J. & Bement, W. M. Wound repair: toward understanding and integration of single-cell and multicellular wound responses. Annu. Rev. Cell Dev. Biol. 27, 237–263 (2011).
5. Wu, N. et al. Critical role of lipid scramblase TMEM16F in phosphatidylserine exposure and repair of plasma membrane after pore formation. Cell Rep. 30, 1129–1140 (2020).

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