Scientists Pinpoint Gene That Triggers Aging

by Kim Boateng Posted on June 28th, 2018

Buffalo, New York, USA: Researchers from University at Buffalo, The State University of New York, have discovered that one particular gene, CD36, triggers the beginning of the phenomenon of senescence in which cells stop dividing. After it is activated, cells stop dividing and start to wither.

There may have been a major scientific breakthrough in understanding aging, as scientists have identified a gene that plays a key role in kick-starting the process that makes cells start turning “old.”

In experiments, University at Buffalo 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 by heightening CD36 activity within those cells. The effect spread to nearby cells, with almost all of the cells in a petri dish showing signs of senescence when only a small fraction of those cells — about 10 to 15 percent — were overexpressing CD36. New cells placed in the growth medium (a soupy substance) that previously housed the senescent cells also stopped replicating.

Senescence is a natural occurrence in the life cycle of every cell. It has long been the focus of medical research, because senescent cells are thought to contribute to a range of ailments, from heart disease and cataracts to arthritis.

The new study, published in the journal Molecular Omics (a journal of the Royal Society of Chemistry), found that CD36 was particularly active in older, senescent cells. The scientists were also able to cause young, healthy cells to quickly act as if they were old by increasing their CD36 activity.

“What we found was very surprising,” one of the researchers, Ekin Atilla-Gokcumen, explained. “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.”

The researchers did not set out to investigate CD36. Rather, they wanted to catalogue all genes related to the aging of cells. They were particularly interested in the lipid-related genes that are involved in this process, because previous studies have shown that lipids play an important role in cellular aging.

CD36 quickly emerged as a gene of interest because it repeatedly popped up in different tests designed to capture the factors that cause cell aging.

First, through a technique called transcriptomics, scientists identified CD36 as one of the two lipid-related genes that ramp up their activity the most in senescent cells.

This part of the study was done on two kinds of cells—human skin and lung fibroblasts—and the findings held true for both cell types. CD36 popped up again in a second test, this one a genetic analysis of all lipid-related genes that kicked into high gear during senescence.

Within this group of genes, CD36 stood out as one of the most variable in humans, meaning that the gene’s DNA sequence is highly likely to vary from person to person. Such diversity may be an indicator of functional variation, in which different environmental and evolutionary pressures give rise to a range of useful mutations in a highly expressed gene that serves an important purpose, Gokcumen says.

“We did not set out to look for CD36,” Gokcumen says. “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.”

While the discovery is exciting, the gene’s exact role in the aging process remains shrouded in mystery. Scientists know that CD36 guides the body in building a protein that sits on the surface of cells, but what exactly the protein does is still being studied. The researchers say the gene represents an exciting topic for deeper research into how cells age.

“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,” said Omer Gokcumen, one of the paper’s authors. “Senescence seems to have implications for old age and cancer, so understanding it is very important.”

“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,” the researchers wrote

In this study, the researchers conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human fibroblast cell lines and at different time points.

The researchers identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines.

The researchers said that their 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.

The researchers further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, the researchers identified one of the upregulated, lipid metabolism genes, CD36, as an outlier.

The researchers 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, the researchers 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, the researchers concluded.

The new study is titled, “An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence”.

Our cover photo shows senescent cells under a microscope. The cells — human lung fibroblasts — became senescent after they or nearby cells were genetically engineered to increase activity of the CD36 gene. Areas stained in blue are regions where an enzyme associated with senescence is active.

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