When cells are exposed to enough chronic stress, cell division can permanently stop. In this cellular limbo state, known as replicative senescence, cells remain alive but no longer proliferate.
Pinpointing the stress factors that cause or accelerate replicative senescence has proven difficult.
Now, in a study to be published on March 30th, cell chemical biology, Scientists at the University at Buffalo have uncovered one such stress factor. They showed that impaired transport proteins and accumulation of lipids known as ceramides may help lock cells into replicative senescence.
Ceramides, a group of fatty molecules, are produced within the endoplasmic reticulum (ER) of cells and transported to the cell’s Golgi complex by ceramide transfer proteins. There, they are converted to another type of lipid known as sphingomyelin.
However, the researchers found that during replicative senescence, this transport process becomes impaired, leading to an accumulation of ceramide within the ER and triggering a stress response.
It is as if the intracellular delivery route is blocked, preventing the ceramide from reaching its proper destination. If these lipid molecules cannot be transported to the Golgi apparatus for processing, they begin to accumulate in the endoplasmic reticulum where they are made. It appears that this accumulation may trigger stress signals that eventually cause cells to stop dividing. ”
Dr. G. Ekin Atilla-Gokcumen, corresponding author of the study, and Dr. Marjorie E. Winkler, Distinguished Professor and Associate Professor in the UB Department of Chemistry
Role in both cell death and cellular limbo
Ceramides are also involved in another cellular process, apoptosis, or programmed cell death. During apoptosis, ceramide accumulates in mitochondria, weakening the mitochondrial membrane. It is a fatal wound from which cells cannot recover.
Atilla-Gokcumen’s team was therefore interested when they first observed that ceramides also accumulate within cells during replicative senescence.
“Ceramides are well known to accumulate in mitochondria during apoptosis, where they help promote cell death,” says Shweta Chitkara, lead author of the study and a medicinal chemistry doctoral student in Athira Gokmen’s lab. “So when we saw that ceramides were accumulating in senescent cells, cells that were alive but not dividing, we had to ask: If ceramides aren’t killing cells, what are they doing?”
The researchers took normally functioning cells and inhibited several enzymes key to ceramide production and metabolism. They wanted to see if blocking any of them would cause replicative senescence.
This experiment ultimately identified the culprit, the ceramide transfer protein. This led the researchers to conclude that transport proteins become impaired during replicative senescence, preventing ceramide from reaching the Golgi apparatus and instead causing it to move back into the ER.
It is thought that this disruption may cause endoplasmic reticulum stress and ultimately lead cells to replicative senescence.
“Thus, ceramide appears to be one molecule that does completely different things depending on whether the cell is reaching the end of its lifespan or the end of its proliferative capacity,” Atila-Gokumen says. “Ceramides are essential for cell function, but only when they are present at the right levels and in the right places, otherwise cell death or cell dysfunction can occur.”
Cause or effect of aging?
Replicative senescence prevents cancer by arresting damaged cells, but the accumulation of senescent cells can contribute to tissue deterioration and age-related diseases.
This study raises an important question: Is inhibition of ceramide transport a deliberate biological mechanism that traps cells in a senescent state, or is it a disruption that occurs as cells age? If defects in lipid transport are found to be responsible for age-related dysfunction, restoring that transport pathway may provide a strategy to rebalance lipid tissues and reverse some of the age-related cellular abnormalities.
“We have shown that interfering with this pathway is sufficient to cause aging,” Atila-Gokumen says. “Understanding whether correcting that disruption can restore healthier cell function is an interesting direction for future research.”
The study was co-authored by Dr. Paras Prasad, State University of New York Distinguished Professor in UB’s Department of Chemistry, Physics, Medicine, and Electrical Engineering. Other co-authors include Dr. Artem Pliss, former UB research associate professor and current assistant professor in the Department of Pharmacy at Université D’Youville. former UB medical chemistry student Natasha Gozali; Mengru Li and Dr. Yasemin Sancak from the University of Washington;
This research was supported by the National Science Foundation.
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Reference magazines:
Chitkara, S. others. (2026). ER-localized ceramide accumulation contributes to replicative senescence. cell chemical biology. DOI: 10.1016/j.chembiol.2026.03.003. https://www.sciencedirect.com/science/article/abs/pii/S2451945626000735?dgcid=author
