Old Cells Gone Bad: Fighting Senescent Cells With CAR-T Technology

(Posted on Monday, December 18, 2023)

Just as we age, so do our cells. These old cells, known as “senescent cells”, can begin to pile up over time, releasing all kinds of inflammatory proteins into our body. Low-level inflammation of this type has been associated with a number of age-related diseases: cancer, cardiovascular disease, osteoarthritis, stroke, and the list goes on. Now, researchers at Sichuan University, China, have developed a promising strategy to break down senescent cells by harnessing CAR-T cell technology, usually used for the treatment of cancer. 

What are Senescent Cells? 

Most of our cells have a natural life cycle. They start out young and energetic, easily completing their respective functions. With time, these same cells become damaged and begin to have difficulty performing as they should. Normally when this happens, the immune system removes the dysfunctional cells so that they can be replaced by a fresh batch. 

Sometimes, however, damaged cells resist removal. Even though they stop multiplying, they don’t die off. Instead, they linger and accumulate, releasing chemicals that trigger inflammation. These are the so-called senescent cells. As our immune system weakens with age, it becomes less adept at clearing dysfunctional cells and the number of senescent cells begins to grow. This is a “global” phenomenon, happening throughout the body, including the brain. 

The threat of these cells is that the inflammation they cause spreads and begins to damage otherwise healthy cells — much like a wildfire starts with a small spark in a dry forest.

Understanding CAR-T Technology

Our immune system has a very clear function: to locate and eradicate any microbial threats or dysfunctional cells, including cancerous cells and senescent cells. To this end, it comes equipped with an extensive quiver of “tools”, or immune cells. Some of these are generalists, deployed at the early stages of an immune response to challenge and slow the spread of potential invaders. Others, the specialists, kick in later. These come ready with specialized receptors that help them detect “antigens”; once they’ve come across an antigen and learned to recognize it, they hold on to the memory. 

T lymphocytes, often abbreviated to T cells, are an example of specialist cells. These come in two lineages, each with its distinct responsibilities. CD4+ “Helper” T cells primarily aid immunity by recruiting other immune cells and by sending them where they are needed most. They act as conductors. CD8+ “Killer” T cells, in contrast, are tasked with the dirty work of directly eliminating microbial and dysfunctional cells. 

The idea behind chimeric antigen receptor (CAR)-T cell therapy is to leverage this destructive power of killer T cells to target and eliminate cells that are otherwise overlooked by the immune system. For example, even though cancerous cells are a risk to us, they are often “too close to home”; our killer T cells simply do not recognize them as a threat. To remedy this, researchers pioneered a novel approach. The first step of this process involves isolating and purifying the necessary killer T cells. This is generally done by collecting a blood sample. Next, the killer T cells are engineered to carry a tailor-made antigen receptor adjusted to recognize the intended target. Finally, the engineered cells are multiplied and then injected back into the patient. Once in the body, the CAR-T cells can locate and destroy their previously “invisible” enemy. 

In theory, the search-and-destroy function of CAR-T cells could also be used for the elimination of other dysfunctional cells that fly under the radar, like senescent cells. 

CAR-T Cells Destroy Senescent Cells

To determine whether CAR-T technology could be used to eliminate senescent cells, the group of scientists engineered CAR-T cells that home in on Natural Killer Group 2 Member D (NKG2D) ligands, which, they discovered, are found in high numbers on senescent cells. 

In vitro tests, performed on human senescent cells grown in petri dishes, showed that the newly developed NKG2D-CAR-T cells successfully managed to diminish the human senescent cells. This held true for all of the senescent cells tested, regardless of the cause of senescence — whether it be cancer-induced, induced by stress from replication, or induced by DNA damage. 

Similar results were seen during in vivo experiments, performed on aged and irradiated mice, both of which have high levels of senescent cells. Treatment of these mice with the NKG2D-CAR-T cells significantly reduced age-associated diseases while simultaneously improving physical performance. Similarly, nonhuman primates treated with the CAR-T cells also displayed a noteworthy decrease in senescent cells without any side effects. 

Takeaways

Although CAR-T technology has quickly risen to prominence in the field of cancer treatment, the full scope of its applications is only just beginning to be explored. The underlying mechanisms, making otherwise invisible cells visible to our immune system, could help treat a whole range of conditions and illnesses. In this study, researchers showed that CAR-T cells may also be adapted to eliminate senescent cells in mouse and primate models. Targeted reduction of senescent cells looks to be a promising new strategy to combat aging and age-related diseases.  

This article was originally published on Forbes and can be read online here.