Senescent cells help to heal damaged tissues

Scientists reappraise the role of “Zombie” cells that anti-aging mMedicine has sought to eliminate

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Senescent immune system cells are potentially among the most harmful of all senescent cells because they spread tissue damage and rapid aging across other body organs and systems. But a discovery by UC San Francisco suggests that not all senescent cells are harmful “zombies.”

While reappraising the role of ‘zombie’ cells that anti-aging medicine has sought to eliminate, scientists found that some are embedded in young, healthy tissues and promote normal repair from damage. 

Scientists have now observed these cells in action in lung tissue and other organs operating as barriers in the body, such as the small intestine, colon, and skin. Lung tissue injuries recover more slowly when treated with senolytic medicines, killing these cells.

Tien Peng, MD, associate professor of pulmonary, critical care, allergy, and sleep medicine, and senior author of the study, said, “Senescent cells can occupy niches with privileged positions as ‘sentinels’ that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair.”

“It was understandable that scientists initially viewed senescent cells as purely detrimental. As people age, senescent cells accumulate characteristics of old, worn-out cells, including the inability to make new cells. Instead of dying like normal aged cells, they live on, spewing a cocktail of inflammatory compounds that form the senescence-associated secretory phenotype (SASP). These factors are linked to Alzheimer’s, arthritis, and other age-related disorders, including cancer. The catchy name “zombie cells” was coined for them.”

Researchers made the amazing discovery that removing senescent cells from mice prevented or reduced age-related disease and increased the animals’ longevity using senolytics that target and kill “zombie cells.” Following that, a surge in activity occurred at research labs and pharmaceutical businesses dedicated to finding and developing more potent versions of these medications.

However, removing senescent cells entails risks. For example, this recent study shown that senescent cells also can promote routine healing by triggering stem cell repair. According to the new research, analytics may negatively impact normal repair, but they also potentially treat disorders where senescent cells are responsible for pathologic stem cell behavior.

Senescent cells can be challenging to investigate since their indicators, such as the gene p16, are sometimes scarce and challenging to find. In early experiments, fibroblastic cells were isolated, grown in culture dishes until there were sufficient numbers of cells for experiments, and then stressed with chemicals that caused senescence in the cells. But in living things, interactions between cells and the tissues around them significantly impact the cells’ gene activity. This means that compared to cells in their normal environment, the features of cells growing in isolation in a glass dish may differ.

To create a more powerful tool for their studies, scientists improved on a common technique of fusing a relevant gene—in this case, the p16 gene, which is overly active in senescent cells—with a green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light. Scientists significantly amplified the fluorescent signal by enhancing the quantity and stability of the green fluorescent protein in these senescent cells. This allowed them to see senescent cells in their natural habitat of living tissues.

The scientists found that senescent cells exist in young and healthy tissues to a larger extent than previously believed and start to develop shortly after birth using this extremely sensitive technology. The scientists also discovered particular growth factors that senescent cells emit to encourage stem cells to proliferate and heal tissues. The revelation that immune system cells like macrophages and monocytes can activate senescent cells is relevant to aging and tissue damage. This finding implies that inflammation in old or injured tissue is a crucial regulator of senescent cell activity and regeneration.

In their studies of lung tissue, Peng’s team observed green glowing senescent cells lying next to stem cells on the basement membrane that serves as a barrier preventing foreign cells and harmful chemicals from entering the body and allowing oxygen to diffuse from the air in the lungs into underlying tissues. Damage can occur at this dynamic interface. The team saw senescent cells in similar positions in other barrier organs, such as the small intestine, colon, and skin. Their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells could not correctly repair the barrier surface.

Endowed Professor in Experimental Pathology said Peng’s study is genuinely significant for aging research, where the goal is to help individuals live longer and healthier lives. 

“The studies suggest that senolytics research should focus on recognizing and precisely targeting harmful senescent cells, perhaps at the earliest signs of disease, while leaving helpful ones intact,” she said. “These findings emphasize the need to develop better drugs and small molecules that will target specific subsets of senescent cells implicated in disease rather than regeneration.”

Journal Reference:

  1. Nabora S. Reyes et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science. DOI: 10.1126/science.abf33
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