Link Between Ceramide Transport and Cell Senescence Could Inform Aging Biology Research

Credit: CIPhotos / iStock / Getty Images Plus When cells experience enough chronic stress, they can stop dividing permanently. In this state of cellular limbo, known as replicative senescence, cells remain alive but no longer proliferate. Pinpointing the stressors that help trigger or accelerate replicative senescence has proven difficult. A study by University at Buffalo scientists has now shed light on one such stressor and demonstrated that an impaired transport protein and a buildup of lipids known as ceramides at the endoplasmic reticulum (ER) can help lock cells into replicative senescence. Led by G. Ekin Atilla-Gokcumen, PhD, Dr. Marjorie E. Winkler Distinguished Professor and associate chair in the UB department of chemistry, the authors suggest their work may point to future research on aging. In their published paper in Cell Chemical Biology (“ ER-localized ceramide accumulation contributes to replicative senescence ,”) the team concluded “By linking ER-localized ceramide accumulation to ER stress signaling, this work uncovers a connection between lipid spatial organization and senescence programming, highlighting organelle-resolved lipid metabolism as a targetable axis in aging biology.” Ceramides, a group of fat molecules, regulate diverse cellular processes through compartment-specific accumulation, the authors wrote. Ceramides are involved in apoptosis, or programmed cell death. “Notably, ceramides localized to the mitochondria induce apoptosis, emphasizing that the cellular localization of ceramides can be linked to their distinct roles in various cellular processes,” the team noted. In addition to apoptosis, ceramides also accumulate in replicative senescence, a state of irreversible cell-cycle arrest. “Several studies have reported amide accumulation during replicative and other senescence programming, implicating these lipids in aging and age-related diseases,” the team continued. “However, the mechanisms by which ceramides and sphingolipids are regulated and function in senescence remain poorly understood.” Ceramides are produced inside cells’ endoplasmic reticulum and transported by the ceramide transfer protein to the cell’s Golgi complex. There, they are converted into another class of lipids known as sphingomyelin (SM). The team’s newly reported research, carried out in human cells, found that during replicative senescence, this transport process becomes impaired, causing ceramides to accumulate inside the ER and trigger a stress response. “It’s as if a delivery route inside the cell becomes blocked, preventing ceramides from reaching their proper destination,” sad corresponding author Atilla-Gokcumen. “When these lipid molecules can’t be transported to the Golgi for processing, they begin to accumulate where they were made, inside the endoplasmic reticulum. That buildup appears to trigger stress signals that can ultimately push the cell to stop dividing.” During apoptosis, ceramides build up at the mitochondria and weaken mitochondrial membranes. It’s a fatal wound from which the cell cannot recover from. “Ceramides are well known for accumulating at the mitochondria during apoptosis, where they help drive cell death,” said the study first author, Shweta Chitkara, a medicinal chemistry PhD student in Atilla-Gokcumen’s lab. “So when we saw ceramides building up in senescent cells, cells that are alive but no longer dividing, we had to ask: If they’re not killing the cell, what are they doing?” To investigate this further, the team took normal functioning cells and inhibited several enzymes key for ceramide production and metabolism. They wanted to see whether shutting any of them off led to replicative senescence. Their experiments eventually yielded a culprit: the ceramide transfer protein (CERT). “Pharmacological inhibition of ceramide transfer protein (CERT), the ER-to-Golgi ceramide transporter, phenocopies sphingolipid remodeling and enhances senescence, suggesting disrupted ceramide trafficking as a driver of senescence,” the investigators wrote. The researchers’ findings led them to conclude that the transport protein becomes impaired during replicative senescence, preventing ceramides from reaching the Golgi and instead causing them to back up inside the ER.  The disruption appears to trigger ER stress that can ultimately push the cell into replicative senescence. “We identify impaired ER-to-Golgi ceramide transport via CERT as a key regulatory node underlying senescence-associated sphingolipid remodeling,” they stated. Atilla-Gokcumen stated, “So it appears that ceramide is one molecule doing very different things, depending on whether a cell is reaching the end of its life or just the end of its proliferative capacity. Ceramides are essential to cell function, but only at the right levels and in the right location, otherwise, you can end up with either cell death or cellular limbo.” Replicative senescence protects against cancer by halting damaged cells, but as senescent cells accumulate, they may contribute to tissue decline and aging-related disease. The study raises a key question: Is disrupted ceramide transport an intentional biological mechanism that locks cells into senescence, or is it a breakdown that occurs as cells age? If faulty lipid trafficking turns out to be a driver of aging-related dysfunction, restoring that transport pathway could offer a strategy to rebalance lipid organization and potentially reverse some age-associated cellular abnormalities. “We’ve shown that interfering with this pathway is enough to induce senescence,” Atilla-Gokcumen commented. “Understanding whether correcting that disruption can restore healthier cellular function is an exciting direction for future research.” News