CAR T-cell therapy makes ageing guts heal themselves

As we age, the cells lining our intestines gradually lose their ability to renew themselves, which is important for maintaining good immunity. But now scientists have reversed this process in old mice using genetically engineered immune cells.

Known as CAR T-cell therapy, it is most often used to treat certain types of blood cancers. This involves collecting a sample of someone's immune cells, called T cells, reprogramming them in the laboratory to target and kill cancer cells, multiplying them, and then injecting them back into the bloodstream. Recently, variations of this technique have also appeared. shows potential for treating solid tumorsand also for preventing clogged arteries and treatment of autoimmune disease lupus.

In this latest study Semir White from Cold Spring Harbor Laboratory in New York State and colleagues wondered about the therapy's potential for restoring function in the aging gut. They wanted to target aging cells. These cells, which accumulate with age, lose their ability to divide but remain metabolically active, releasing chemicals that promote inflammation and accelerate further aging. To get to them, the team targeted a protein called uPAR, which is present on the surface of aging cells.

“The decline we see in the aging gut is a deficiency in the fitness of the stem cells that renew the gut lining every three to five days,” says Beyaz. “We hypothesized that removing unfit senescent cells would increase the regenerative capacity and fitness of stem cells in aged mice.”

To test this idea, the researchers generated CAR T cells in aged mice so that they would recognize uPAR on senescent cells and remove them. After the engineered cells were reintroduced into the mice, they noticed that it restored the activity and number of their stem cells, which support tissue function, to levels reminiscent of younger mice. It also improved markers of intestinal barrier integrity and inflammation in these elderly mice to a greater extent than in another group of elderly mice that received CAR T-cell therapy that did not specifically target uPAR.

“When we removed these [senescent] Using engineered CAR T cells, we not only stopped the aging process, but also observed a reversal of the process, where the tissue began to behave in the same way as in young mice,” says a member of the team. Corina Lovealso at Cold Spring Harbor Laboratory.

“This may ultimately improve the decline in gut function associated with aging, which may reduce susceptibility to diseases such as intestinal infections, deterioration of intestinal structural integrity, and even cancer,” says Tuomas Tammela at Memorial Sloan-Kettering Cancer Center in New York, which was not involved in the study. But he adds that researchers need to demonstrate that this approach is also effective and safe in humans.

Team Member Onur Eskiokakalso from the Cold Spring Harbor Laboratory, says it is especially important to determine the optimal “dose” of a therapy before it can be tested in humans. “Although uPAR is highly enriched in senescent maladjusted cells, low levels of uPAR expression may also exist in normal tissues and other conditions,” he says.

Senescent cells aren't always bad news either: they've been linked to tumor suppression And wound healing. “There is no reporting [by the researchers] what happens in other tissues where uPAR-positive is depleted,” says Jesse Pagan at Harvard Medical School.

We also don't usually treat aging itself in a healthy person. Moreover, CAR-T therapy is expensive and logistically challenging. This, along with ongoing safety concerns, means the approach likely won't be widely adopted anytime soon for indications such as reversing the effects of aging, he says. Joana Neves at King's College London. “For preventive indications or quality of life indicators, the safety bar is higher than in oncology.”

But Beyaz says reversing the decline of gut function with age has been a long-standing goal, especially because he says there are no effective treatments that support the gut barrier. health when its regenerative capacity is impaired. “This study is a step in the right direction, demonstrating that we can restore this vital function by removing unusable cells that contribute to aging,” he says.