Senescent cells also help to heal damaged tissues

Not all senescent cells are harmful “zombies” that must be eradicated to prevent age-related diseases, new research from UC San Francisco shows, which found that some of them are embedded in young, healthy tissues and promote normal repair from damage.

Scientists have now seen these cells in action in lung tissue, as well as other organs that serve as barriers in the body, such as the small intestine, colon and skin. When they used drugs called senolytics to kill these cells, injuries to lung tissue healed more slowly.

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

Aged cells can both damage and heal

Peng said it was understandable that scientists initially viewed aging cells as purely harmful. As people age, senescent cells build up that have characteristics of old, worn-out cells, including the inability to make new cells. Instead of dying like normal old cells, they live on and spew out a cocktail of inflammatory substances that form the senescence-associated secretory phenotype (SASP). These factors have been linked to Alzheimer’s disease, arthritis and other age-related diseases, including cancer. The catchy name “zombie cells” was coined for them.

Using senolytics that target and kill “zombie cells,” researchers made the exciting discovery that clearing aging cells from animals thwarted or reduced age-related diseases and extended the animals’ lifespan. This was followed by a boom of activity in research labs and pharmaceutical companies focused on discovering and refining more potent versions of these drugs.

But killing senescent cells has dangers, Peng said. First, this current study showed that senescent cells also have the ability to promote normal healing through activation of stem cell repair. “Our study suggests that senolytics may adversely affect normal recovery, but they also have the potential to target diseases in which senescent cells drive pathological stem cell behavior,” Peng said.

Light up aging cells

A major challenge in studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite scarce, making it difficult to detect the cells. In early experiments, researchers extracted cells called fibroblasts into culture dishes, which allowed them to grow and produce enough cells to experiment with, then stressed the cells with chemicals that caused them to age. But in living organisms, cells interact with tissues around them, greatly affecting the cells’ gene activity. This means that the properties of cells growing in isolation in a glass dish can be quite different from those of cells in their natural environment.

To create a more powerful tool for their studies, postdoctoral scientist Nabora Reyes de Barboza, PhD, and colleagues improved a general technique to target a relevant gene — in this case, the p16 gene, which is overly active in senescent cells. fuse with green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light. By increasing the amount and stability of green fluorescent protein in these senescent cells, Reyes greatly amplified the fluorescent signal, allowing the researchers to finally see senescent cells in their natural habitat of living tissues.

‘Zombies’ stimulate stem cells shortly after birth

Using this highly sensitive tool, the researchers found that senescent cells occur in young and healthy tissues to a greater extent than previously thought, and actually begin to appear shortly after birth. The scientists also identified specific growth factors that aging cells secrete to stimulate stem cells to grow and repair tissues. Relevant to aging and tissue damage is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation observed in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.

In their research on lung tissue, Peng’s team observed green glowing senescent cells lying next to stem cells on the basement membrane that serve as a barrier that prevents foreign cells and harmful chemicals from entering the body and also allows oxygen from the air in the lungs to diffuse into the lungs. lungs. underlying tissues. Damage can occur with this dynamic interface. The team saw senescent cells in similar positions in other barrier organs such as the small intestine, colon and skin, and their experiments confirmed that when senescent cells were killed with senolytics, lung stem cells failed to properly repair the barrier surface.

Leanne Jones, PhD, director of the UCSF Bakar Aging Research Institute and Stuart Lindsay endowed professor of experimental pathology, said Peng’s study is really important for aging research, where the goal is to help individuals live longer and healthier lives.

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

Reference: Reyes NS, Krasilnikov M, Allen NC, et al. Sentinel p16 INK4a+ cells in the basement membrane form a restorative niche in the lung. Science. 2022;378(6616):192-201. doi: 10.1126/science.abf3326

This article has been republished based on the following materials. Note: Material may have been edited for length and content. For more information, please contact the said source.

Leave a Comment