According to a recent study from the University of California, San Francisco, not all senescent cells are detrimental “zombies” that need to be eliminated to avoid age-related diseases. Instead, some of them are embedded in young, healthy tissues and promote normal recovery 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 employed drugs known as senolytics to eliminate these cells, lung tissue damage healed more slowly.
“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,” said Tien Peng, MD, associate professor of pulmonary, critical care, allergy and sleep medicine, and senior author of the study, which was recently published in the journal Science.
It’s understandable, according to Peng, that scientists initially saw senescent cells as purely harmful. Senescent cells, which have the characteristics of old, worn-out cells and the inability to make new cells, accumulate as humans age. Instead of dying, they live on, spewing a mix of inflammatory substances that form the senescence-associated secretory phenotype (SASP). These variables have been linked to Alzheimer’s disease, arthritis, and other age-related diseases such as cancer. They were given the catchy name “zombie cells.”
Using senolytics, which target and destroy “zombie cells,” researchers discovered that removing senescent cells from animals prevented or reduced age-related disease and increased the animals’ lifespan. Following that, there was a surge of activity in research laboratories and pharmaceutical companies focused on discovering and refining more potent versions of these drugs.
But killing off senescent cells has dangers, Peng said. For one thing, this current study showed that senescent cells also possess the ability to promote normal healing through the activation of stem cell repair. “Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behavior,” said Peng.
One major challenge to studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite sparse, making it difficult to detect the cells. In early experiments, researchers extracted cells called fibroblasts into culture dishes, allowing them to grow and produce enough cells to experiment with, and then stressed the cells with chemicals that induced them to become senescent. But in living organisms, cells interact with tissues around them, strongly affecting the cells’ gene activity. This means that the characteristics of cells growing isolated in a glass dish could be quite different from that of cells in their natural environment.
To create a more powerful tool for their studies, postdoctoral scholar Nabora Reyes de Barboza, Ph.D. and colleagues improved on a common technique of fusing a relevant gene—in this case, the p16 gene, which is overly active in senescent cells—with green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light. By enhancing the quantity and stability of green fluorescent protein in these senescent cells, Reyes greatly amplified the fluorescent signal, finally enabling the researchers to see senescent cells in their natural habitat of living tissues.
Using this highly sensitive tool, the researchers found that senescent cells exist in young and healthy tissues to a greater extent than previously thought, and actually begin appearing shortly after birth. The scientists also identified specific growth factors that senescent cells secrete to stimulate stem cells to grow and repair tissues. Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier 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 also allows 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, and their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells were not able to properly repair the barrier surface.
Leanne Jones, Ph.D., director of the UCSF Bakar Aging Research Institute and Stuart Lindsay Endowed Professor in Experimental Pathology, said Peng’s study is truly significant for the field of aging research, where the goal is to help individuals live longer and more healthy 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 that are implicated in disease rather than in regeneration.”
Reference: “Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung” by Nabora S. Reyes, Maria Krasilnikov, Nancy C. Allen, Jin Young Lee, Ben Hyams, Minqi Zhou, Supriya Ravishankar, Monica Cassandras, Chaoqun Wang, Imran Khan, Peri Matatia, Yoshikazu Johmura, Ari Molofsky, Michael Matthay, Makoto Nakanishi, Dean Sheppard, Judith Campisi and Tien Peng, 13 October 2022, Science.
The study was funded by the National Institutes of Health.
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