Developmental biology - Cell Aging|
Unlocking Secrets of Cell Aging
Cells stop dividing when this gene kicks into high gear...
Cells stop dividing when one specific gene kicks into high gear. This discovery centers on a gene called CD36, illuminating a process of cell aging that stops cells from dividing.
Senescence, deterioration with age, is a natural process in the life of a cell. Researchers seek to learn about it for two reasons. First, it is connected to old age as senescent cells are thought to contribute to heart disease, arthritis, cataracts and many other age-linked conditions. Second, it is a hallmark of cancer when cells cannot die and replicate in an uncontrolled manner.
The new study - published online on June 20 in Molecular Omics, a journal of the Royal Society of Chemistry - illuminates genes involved in cellular senescence, and highlights one in particular that seems tightly associated with this crucial biological process.
In experiments, University at Buffalo (UB) researchers discovered that a gene called CD36 is unusually active in older, senescent cells.
What's more, scientists were able to cause young, healthy cells to stop dividing simply by exposure to CD36 cells. The senescence effect spread with almost all cells showing signs of senescence although the initial cell population had only 10 to 15 percent of cells with overexpression of CD36. New, healthy cells added to the petri dish also stopped replicating.
"What we found was very surprising. Senescence is a very complex process, and we didn't expect that altering expression of one gene could spark it, or cause the same effect in surrounding cells."
Ekin Atilla-Gokcumen PhD, Assistant Professor of Chemistry, University at Buffalo College of Arts and Sciences, and study leader.
The results point to CD36 as an exciting area for future research. The gene's exact role in senescence remains a mystery. Scientists know that it guides the body in building a protein of the same name which sits on the surface of cells, but that protein's functions are still being studied. Proposed processes activated by the CD36 protein include helping cells import lipids (fatty acids or their derivatives), and influencing how these lipids are used within cells.
"Our research identifies CD36 as a candidate for further study. Senescence is a fundamental aspect of being a cell, but there is still a lot that we don't know about it. Senescence seems to have implications for old age and cancer, so understanding it is very important."
Omer Gokcumen PhD, Assistant Professor, Biological Sciences, University at Buffalo College of Arts and Sciences and co-leader of the study.
Atilla-Gokcumen and Gokcumen together led the research. First authors were UB chemistry PhD student Darleny Lizardo and UB biological sciences postdoctoral researcher Marie Saitou, who also won an award for her talk on this work during the UB Postdoctoral Research Symposium June, 2018.
Zeroing in on an important gene
The scientists did not set out to investigate CD36. Instead, they began with two goals: (1) to catalogue all genes related to senescence, and (2) gain a better understanding of lipid-related genes involved in senescence. Past studies had shown lipids play a role in cellular aging, andCD36 emerged as a gene of interest in experiments designed to address those questions.
Through a technique called transcriptomics, scientists identified CD36 as one of the two lipid-related genes that ramp up activity highest in senescent cells. Human skin and lung fibroblast cells were used in this aspect of the research and resulting findings held true for both cell types.
In a second test analysing genetics of all lipid-related genes that kick into high gear during senescence, CD36 popped up again. Within this group of genes, CD36 stood out as one of the most variable of human genes, in that the CD36 DNA sequence is highly likely to vary from person to person. Such diversity may be an indicator of functional variation, where different environmental and evolutionary pressures give rise to a range of useful mutations in a highly expressed gene that serves an important purpose.
Gokcumen: "We did not set out to look for CD36. We took a broad approach to our study, using transcriptomics and an evolutionary framework to identify genes and proteins that are fundamental to the senescence process. In the end, CD36 stood out as an outlier in both cases. That's kind of beautiful - a compelling way to do biological research."
Cellular senescence, the irreversible ceasing of cell division, has been associated with organismal aging, prevention of cancerogenesis, and developmental processes. As such, the evolutionary basis and biological features of cellular senescence remain a fascinating area of research. In this study, we conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human fibroblast cell lines and at different time points. We identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines. Our functional enrichment analysis showed that downregulated core genes are primarily involved in cell cycle processes while upregulated core gene enrichment indicated various lipid-related processes. We further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, we identified one of the upregulated, lipid metabolism genes, CD36, as an outlier. We found that overexpression of CD36 induces a senescence-like phenotype and, further, the media of CD36-overexpressing cells alone can induce a senescence-like phenotype in proliferating young cells. Moreover, we used a targeted lipidomics approach and showed that phosphatidylcholines accumulate during replicative senescence in these cells, suggesting that upregulation of CD36 could contribute to membrane remodeling during senescence. Overall, these results contribute to the understanding of evolution and biology of cellular senescence and identify several targets and questions for future studies.
Authors: Marie Saitou, Darleny Y Lizardo, Recep Ozgur Taskent, Alec Millner, Omer Gokcumen and Gunes Ekin Atilla-Gokcumen.
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Jun 28, 2018 Fetal Timeline Maternal Timeline News News Archive
Human lung fibroblast cells begin dying when they, or nearby cells, are exposed to the CD36 protein. Areas stained in blue are regions where an enzyme associated with senescence is active. Image: Darleny Lizardo/Alan Siegel, University at Buffalo, Confocal Imaging Facility.