A Breakthrough Discovery Reveals the Secret of Cellular Aging in Phospholipid Membranes

Japanese scientists have discovered a previously unknown fate of damaged cells that could significantly change our understanding of aging, disease and how the body heals itself.

Scientists from the Okinawa Institute of Science and Technology (OIST) and a team of researchers from the University of Tokyo, Nagoya University, and Nagoya City University have discovered an interesting fact: damage to the cell membrane affects the aging process of cells. This groundbreaking study was published in the prestigious journal Nature (https://doi.org/10.1038/s43587-024-00575-6).

The key interface of the cellular world

The cell membrane is a thin and elastic barrier that surrounds each cell. It acts as a gatekeeper, allowing certain substances in and out while preventing others from passing through. The membrane is predominantly made of bilayers of phospholipids and lipids. The membrane also contains proteins that act as transporters through the membrane and loosely attached peripheral enzymes that enable interaction with the world outside of the membrane. Although the membrane protects the cell, it is susceptible to damage during daily activities due to muscle contractions, injury, infection, chemical exposure, thermal shock, radiation, oxidative stress, and other factors. A team of Japanese scientists, therefore, focused on understanding what happens when cell membranes suffer damage and how this affects cell fate.

Yeast and genes

The researchers used baker’s yeast as a model to examine how different genes affect the ability of cells to repair membrane damage. They found that some genes play a key role in protecting cells from damage and can even extend the lifespan of cells. Yeast lacking these genes were more sensitive to membrane-damaging chemicals. Conversely, yeast with excessive activity of membrane repair genes lived longer.
Other experiments focused on human cells, specifically lung and skin fibroblasts. The team found that even in these cells, membrane damage can lead to premature aging and changes in cell function.

Fate of damaged cells

Previously, it was thought that mechanical damage to the cell membrane could only lead to two simple scenarios: either healing or cell death. However, in this research, the researchers discovered an unexpected third consequence – cellular aging.
“When I started this project, I simply wanted to understand the mechanisms of repairing a damaged cell membrane,” recalls Professor Keiko Kono, Head of the Department of Membranology at OIST and lead author of the study. “Unexpectedly, we ended up finding that damage to the cell membrane affects the future of the cells.”
According to scientists, the fate of cells depends on the extent of damage and the subsequent influx of calcium ions.
Minor damage to the thin cell membrane can be easily repaired, allowing cells to continue cell division without problems. The highest degree of cell membrane damage induces cell death. However, a moderate level of damage puts the cells into a state of senescence (biological aging) after a few days, even though membrane re-healing appears to be successful.

Like a zombie

Senescent cells, also known as “zombie cells”, are still metabolically active, but unlike healthy cells, they secrete specific proteins that affect the body’s immune responses. This process can have both positive and negative effects; on the one hand, they can speed up wound healing, and on the other hand, they can contribute to the aging process and increase the risk of cancer. This could explain why senescent cells often accumulate around wounds and areas of damage—at least initially, they may play a useful role there.
In recent years, research suggests that removing these cells can lead to the rejuvenation of bodily functions in both animals and humans, but the exact mechanism of cellular aging remains a debated topic.

Unveiling the mechanism of aging

The most common trigger of cellular aging is repeated cell division. Many other factors such as DNA damage, oncogene activation and epigenetic changes can induce senescence in laboratory conditions. All these stresses have long been believed to lead to cellular aging by triggering the DNA damage response. However, the authors of the study made a surprising discovery: they found that damage to the cell membrane can cause cellular aging in a completely different way, through calcium ions and a gene that protects the organism from the formation of tumors.
When the cell membrane is damaged, calcium enters it from the outside. This calcium activates the p53 gene, a key protein sometimes called the “guardian of the genome” because it oversees the proper functioning of cells and can trigger various protective mechanisms in case of danger. P53 then initiates the production of another protein called p21. This protein acts as a kind of brake pedal that forces the cell cycle to stop, which means that the cell stops dividing.

The path to healthy longevity

Interestingly, the researchers discovered that this reaction can be prevented by using a compound that binds to calcium ions, so the cell’s ability to divide is not blocked. These findings may contribute to the development of strategies to achieve healthy longevity in the future. For example, it was further noted that quick resealing of the damaged cell membranes would prevent calcium ions from entering the cells, stopping their ability to divide and contributing to aging.
In other words, a healthy cell membrane is critical to healthy cells and to extending their lifespan. Proper phospholipid nutrients that can help reseal the membranes can play a crucial role in this effort and help to prevent cellular aging.