The accumulation of senescent cells with age causes age-related disease and dysfunction. The most important factor driving this accumulation may be the decline of the immune system, as immune cells are responsible for cleaning up the tiny fraction of all senescent cells that fail to self-destruct, but that has yet to be determined with any great rigor. Regardless of the reasons for this accumulation, periodic removal of senescent cells has been shown to improve health and extend life span in mice, as well as reverse specific aspects of tissue aging in a variety of organs. Therefore a great deal of interest is currently focused on finding new and better ways to go about the targeted destruction of senescent cells. That starts with further mining of the biochemistry of these cells, such as in the research results noted here.
There are at present a limited number of proven approaches to senolytic therapies, those that can selectively destroy senescent cells without causing any great harm to normal cells. Immunotherapy targeting surface markers on senescent cells, as at SIWA Therapeutics, suicide gene therapy tied to expression of senescence-associated proteins inside senescent cells, as at Oisin Biotechnologies, and small molecule / pharmacological approaches, as at Unity Biotechnology. Of these, the latter has the broadest variety at the moment, each class of pharmaceutical targeting a different mechanism associated with senescence, usually those involved in holding back programmed cell death in lingering senescent cells.
In the pharmacological camp, the known mechanisms include: the Bcl-2 inhibition common to most of the repurposed chemotherapeutics, such as navitoclax; whatever it is that dastinib is doing under the hood instead of Bcl-2 inhibition, not well understood at this time; interfering in the FOXO4-p53 interaction; interfering in the MDM2-p53 interaction; and so forth. Anyone turning up a new approach beyond these few, and people will do just that, since all molecular mechanisms inside cells have many surrounding connections, has the potential to create in a lucrative line of research and development. The market for a working rejuvenation therapy based on removal of senescent cells is so large that many competing approaches could thrive, and all of the existing pharmacological approaches under development could be improved upon. That is the incentive for further exploration of the detailed biochemistry of cellular senescence, and why much more funding is available for that line of work these days.
Senescence is a natural occurrence in the life of a cell, and researchers have sought to learn about it for a couple of reasons. First, it's connected to old age: Senescent cells are thought to contribute to heart disease, arthritis, cataracts, and a bevy of other age-linked conditions. Second, a lack of senescence is a hallmark of cancer cells, which bypass this process to replicate in an uncontrolled manner.
A new study illuminates genes involved in cellular senescence, and highlights one in particular that seems tightly associated with this crucial biological process.In experiments, researchers discovered that a gene called CD36 is unusually active in older, senescent cells. What's more, the 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 that previously housed the senescent cells also stopped replicating.
The results point to CD36 as an exciting topic of future research. The gene's exact role in senescence remains a mystery: Scientists know that the gene guides the body in building a protein of the same name that sits on the surface of cells, but this protein's functions are still being studied. Proposed activities include helping cells import lipids, and influencing how these lipids are used within cells.
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.