Maybe we shouldn’t be surprised that so-called “zombie cells” come with a catch. In response to severe damage, when cells can’t recover full function but aren’t ready to die, they can become senescent, in a zombie-like state between life and death.
In young, healthy people, this is a protective mechanism, stopping damaged cells from proliferating into cancers. A strong immune system can clear these cells efficiently, preventing them from affecting nearby tissues. But with age, our immune systems become less effective at removing them—and that’s where the trouble begins.
“Even a small percentage of these cells in tissues can wreak a lot of havoc,” explains HHMI Freeman Hrabowski Scholar Corina Amor Vegas. When senescent cells linger, they trigger aging’s most damaging symptoms, including chronic inflammation, frailty, metabolic decline and cognitive loss.
Researchers are testing small-molecule drugs that can effectively eliminate senescent cells, but these treatments can also affect healthy cells and require ongoing redosing, which may limit effectiveness over time.
Amor Vegas was interested in finding another path to clear senescent cells. She reasoned that if the problem lies in the immune system’s response—not the cells themselves—the solution might lie there, too.
Taking a page from cancer therapy’s book
In CAR-T cell therapy—which has become a common blood cancer treatment in the last decade—a patient’s own immune cells are genetically engineered to better recognize and attack cancer. The synthetic receptor (the chimeric antigen receptor, or CAR) is attached to the surface of the patient’s T cells, allowing them to recognize and bind to specific proteins on tumor cells.
Once CAR-T cells are reintroduced into the body, the modified T cells can multiply and continue to hunt down cancer cells over long periods.
For Amor Vegas, the longevity of CAR-T cells was a major draw. But there was a challenge: CAR-Ts need to find the right protein to bind to.
A surface protein called uPAR offered an exciting potential solution. uPAR, which stands for urokinase-type plasminogen activator receptor, becomes highly expressed in cells that have transitioned to specific states, including senescence.
By engineering cells that target uPAR specifically, the CAR-Ts take aim at senescent cells while leaving most normal cells alone. The aging mice that received the CAR-T treatment became physically stronger, and their metabolic function also improved.
Going for the gut
Armed with this proof of concept, Amor Vegas and her team at Cold Spring Harbor Laboratory are striving to understand how exactly the CAR-T cells work, and where. It quickly became apparent that CAR-T cells are better absorbed in some parts of the body than others. They have trouble crossing the blood-brain barrier, for example, but are quite successful in the liver.
The gut epithelium seemed like another particularly promising area for CAR-T cell interventions. A common symptom of aging, in animals and humans alike, is the development of glucose intolerance.
Amor Vegas found that, as both a preventive measure and a response to existing dysfunction, CAR-T cells improved gut function, reduced inflammation, and strengthened the cells’ regenerative capacities.
From promise to practice
Like any therapy, CAR-T cells have drawbacks. At the high doses needed for cancer treatment to combat tumors, they can sometimes be toxic, triggering cytokine release syndrome. But in aging, where there are far fewer senescent cells to target, much lower doses appear to be effective—and potentially far safer.
It will take time before this treatment can be considered for people, not only because of safety considerations, but because scientists will need to identify the right targets in the body and fully consider any immune interactions that might occur.
But the potential of this treatment is compelling, particularly because it represents a possible long-term solution to the symptoms associated with aging. “Because the CAR-Ts are addressing a lower target burden in senescence than they are in cancer, they also have more stamina to fight their target cells again later,” explains Amor Vegas. “That’s one of the coolest things about the CARs: They develop memories, and they can persist for years.”
If all goes well, maybe in time, CAR-Ts will finally lay those uncleared zombie cells to rest.
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