“Zombie” Cells Eliminated With New Molecule

Over time, the body's cells stop working properly and begin to accumulate, which eventually leads to tissues ageing. Researchers at the UOC collaborating with the University of Leicester (United Kingdom) have discovered a new molecule that is able to destroy these old cells without affecting the healthy ones. This paves the way to being able to delay the ageing of the body's tissues and eventually, to improving quality of life and life expectancy in human beings. For now, the results, which have been published in open-access format in the journal Aging, have been obtained in cells in vitro, and testing with animal models will now begin.

During a person's life, cells undergo various types of stress, such as solar radiation, which leads to them accumulating mutations. The body activates defence mechanisms at a certain point in order to prevent a tumour from developing: either the cell 'commits suicide', in a process known as apoptosis, or it becomes senescent, which is a kind of 'zombie' state between life and death, in which it no longer functions despite still being alive, and it also begins to manufacture products that replicate the zombie state in the other healthy cells around it. While the organism is young, the immune system can eliminate these cells and clean up the tissues.

However, as people get older, the immune system stops performing this maintenance; the reasons why this happens are unknown. This means that these zombie cells begin to accumulate in our tissues, impairing how they work, and leading to ageing.

Studies in animals have shown that with the administration of drugs called senolytics, which are able to eliminate these old cells, it is possible to improve the life expectancy and quality of life of animals.

The researchers, led by Professor Salvador Macip, dean of the UOC's Faculty of Health Sciences and Professor of Molecular Medicine at the University of Leicester, have identified a molecule called CUDC-907 that destroys old cells quite efficiently and specifically, with few side effects on healthy cells.

"The drug we identified is a powerful destroyer of old cells and its effect against some cancers is also now being investigated, so it could have a double effect: anti-cancer and at the same time, it could act against old cells that make the cancer reappear," said Macip.

In cancer, this drug, which acts by inhibiting two cell communication pathways – one of which was hitherto unknown and has been discovered by Macip's team – was being investigated in order to eliminate the cells that are extensively damaged by chemotherapy or radiotherapy treatment but which do not die, and instead become senescent, which may lead to a tumour appearing again. "This drug could be administered with chemotherapy or radiotherapy to destroy these zombie cells and by doing so, considerably reduce cancer relapses," said Macip.

In this study, the researchers used different models of human cancer cells, and found that dual inhibitor CUDC-907 eliminates a specific type of senescent cell with limited side effects. They will now begin tests with animal models, and if they obtain good results, they will then test it with humans. The researchers believe that the drug could also be applied in diseases where the accumulation of senescent cells plays a role, such as Alzheimer's disease.

"Perhaps an intensive dose of the drug would clean the brain and prevent the disease from progressing. It could also be useful in idiopathic pulmonary fibrosis, to slow its progress, rather than the ageing itself," said Macip.

Reference: Al-Mansour F, Alraddadi A, He B, et al. Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging. 2023;15(7):2373-2394. doi: 10.18632/aging.204616

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