New research has scientists reconsidering the role of ‘zombie’ cells that drive some aspects of aging and whether they should be eliminated using senolytic drugs. It turns out that not all senescent cells are necessarily bad and that some may be helpful.
Introducing zombie cells
As we get older, more and more of our cells become senescent. Our cells should destroy themselves when they reach senescence, but, as we age, increasing numbers of them evade this process and become ‘zombie’ cells that refuse to die.
These cells do not divide, and they secrete an inflammatory cocktail of signals called the senescence-associated secretory phenotype (SASP). The SASP can contribute to age-related diseases and cause nearby healthy cells to become senescent, and their presence is thought to be one of the reasons we age.
One proposed solution to the problem is senolytics: drugs that specifically eliminate senescent cells. There has been a great deal of interest in developing senolytic drugs that can target senescent cells and destroy them.
Originally, it was thought that all senescent cells were harmful and supported the development of age-related diseases. Indeed, early senolytic experiments in mice that removed these cells delayed age-related diseases and increased the lifespan of the animals.
These initial results spurred great interest in developing senolytics with the hope that those beneficial effects might be translated to people. However, it turns out that not all senescent cells are harmful and that some could be beneficial. In other words, simply destroying them all with senolytics may not be the best approach.
Senescent cells healing or harmful
New research from UC San Francisco suggests that some senescent cells present in healthy tissue promote tissue repair following damage .
The researchers observed senescent cells in the tissues of the lungs, small intestine, colon and skin. When they used senolytic drugs to kill the senescent cells, it caused those tissues to heal injury slower.
The results of the study suggest that some senescent cells can act as ‘sentinels’ and sit in the tissue watching for signs of injury. When damage to the tissue occurs, these sentinels then respond by signaling nearby stem cells to engage their growth and repair systems.
The study authors caution that destroying senescent cells has some risks. On one hand, they suggest that senolytics have the potential to cause tissue dysfunction and hinder tissue repair. On the other hand, they also propose that senolytics may be able to address age-related diseases driven by senescent cells.
Identifying senescent cells by making them glow
One of the hurdles in studying senescent cells is being able to spot them among the thousands of regular cells in tissues. An ongoing challenge for the field has been to establish reliable biomarkers of senescence so that these cells can be identified.
For example, the p16 gene is often used as a biomarker of senescence, as it is typically very active in these cells, but this can be hard to detect, and other cells can also express it under certain conditions. What the researchers needed was a better way to identify senescent cells in tissue. Using a lab technique, they fused the p16 gene with green fluorescent protein (GFP) and amplified the fluorescence further. GFP glows under ultraviolet light, making it easier to see the senescent cells in tissues.
Using the GFP method, the researchers discovered that senescent cells are actually present in young tissues and in greater numbers than previously assumed. The research team found that they began to appear not long after birth, which is somewhat surprising given that they are typically associated with old age. The researchers also identified a number of growth factors that were being secreted by the senescent cells, signaling stem cells to activate and promote growth and repair.
Senescent cells play an important role in tissue repair
While examining lung tissue, the team noticed that glowing senescent cells were located next to stem cells in the basement membrane. This membrane acts as a barrier to stop chemicals, bacteria, and other pathogens from entering the body. It also allows oxygen in the lungs to diffuse into the tissues below. The researchers observed that senescent cells were also occupying similar positions in other barrier tissues in other organs like the colon, small intestine, and skin.
This barrier can become damaged, and this is where senescent cells play an important role. The scientists found that if they killed the senescent cells in the lung tissue using senolytics, the stem cells were then unable to repair the barrier surface properly.
These results suggest that indiscriminate use of senolytics is a risky proposition and that research needs to focus on making them highly selective as to which cells it targets. Simply dumb-firing senolytics and killing all senescent cells is asking for trouble, as the results of this study support.
To be successful, not only must the harmful subsets of senescent cells be identified, senolytic drugs must be developed that only kill those cells and not ones serving a useful purpose. It should also serve as a cautionary tale for people engaging in self-experimentation with senolytics.
We engineered an ultrasensitive reporter of p16INK4a, a biomarker of cellular senescence. Our reporter detected p16INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung.
Furthermore, these p16INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration.
In addition, p16INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.
This study highlights that we currently do not have a full understanding of senescent cells and thier various roles in aging and repair. In any given tissue, there are various kinds of senescent cells, each using different pro-survival pathways.
Understanding these cell populations will help researchers determine which ones might be safely removed using senolytics and which should be left alone. The potential of senolytics to slow down aging and improve health is still on the cards, but it seems ever more likely that simply destroying all senescent cells is a bad idea.
The Campisi lab at the Buck institute for Research on Aging has been busy the last few years trying to work out the complexities of senescent cell populations. In 2020, they collaborated with other researchers to make a SASP Atlas, which is a step closer to understanding senescent cells .
Biology is never simple, and there is often more than one solution to a problem. Senolytics may yet prove their worth in the push to defeat age-related diseases; this study just serves to remind us that we have more to learn before we can do that.
 Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., Ravishankar, S., Cassandras, M., Wang, C., Khan, I., Matatia, P., Johmura, Y., Molofsky, A., Matthay, M., Nakanishi, M., Sheppard, D., Campisi, J., & Peng, T. (2022). Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science (New York, N.Y.), 378(6616), 192–201. https://doi.org/10.1126/science.abf3326
 Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., Campisi, J., & Schilling, B. (2020). A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS biology, 18(1), e3000599. https://doi.org/10.1371/journal.pbio.3000599