Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Senescent cells physiologically inhibit tumor development, but excessive accumulation induces chronic inflammation. In this study, urokinase-type plasminogen activator receptor (uPAR) was used as the target of chimeric antigen receptor (CAR) T cells to identify senescent cells, and both in vivo and in vitro experiments can effectively remove senescent cells. CAR T cells targeting uPAR can improve the survival rate of lung adenocarcinoma mice treated with aging-inducing drugs and restore liver fibrosis in mice to tissue homeostasis. This result suggests the potential of senolytic CAR T cells to treat aging-related diseases.

Figure 2-1 Genes encoding surface molecules that are commonly upregulated in senescence

More than 10 years ago, scientists discovered that there is a type of "senescent cells" in animals. They are no longer split and no longer work properly. On the contrary, they will spread "negative energy" around, releasing some toxic cytokines, causing inflammation around them, and even damaging the DNA of surrounding cells.

Scientists believe that age-related diseases such as osteoarthritis, atherosclerosis, and even diabetes are related to these senescent cells. Therefore, the pharmaceutical industry is developing "anti-aging drugs" to kill these senescent cells and revitalize the body.

Today the research published in Nature uses a cell therapy called CAR-T to kill senescent cells.CAR-T was originally a breakthrough anti-cancer therapy. Its working principle is easy to understand-we use gene editing technology on immune T cells to install golden eyes (that is, CAR) to identify cancer cells. In this way, CAR-T therapy can specifically target these cancer cells, induce an immune response, and kill them.

Then we change our thinking. If we can teach CAR-T cells to recognize senescent cells, can we turn anti-cancer therapy into anti-aging therapy?

That's what researchers think. The first step they did was to look for features on the surface of senescent cells. After a series of screenings, they discovered that a cell surface receptor called uPAR is the "identity card" of senescent cells. In the process of aging, the level of this molecule will also rise.

Figure 2-2 uPAR is a cell-surface and secreted biomarker of senescence

Subsequently, the scientists developed a CAR-T cell therapy for uPAR and determined that this therapy can effectively eliminate uPAR-expressing cells in cell experiments.

One of the diseases the researchers chose was fibrosis of the liver. This is a chronic disease that is affected by aging, and it will slowly develop into liver cirrhosis and even liver cancer! In the mouse model, the scientists injected a new type of anti-aging cell therapy and found that compared with the control group, the level of liver fibrosis in the mice was significantly improved!

Figure2-3 Senolytic CAR T cells show therapeutic activity in CCl4-induced liver fibrosis