CAR T-cell therapy makes ageing guts heal themselves

As we age, the cells that line our intestine gradually lose their ability to renew themselves, which is important for maintaining good immune health. But now, scientists have reversed this process in older mice using genetically engineered immune cells.

Known as CAR T-cell therapy, this is most commonly used to treat some kinds of blood cancer. 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 infusing them back into the bloodstream. Variations on the technique have also recently shown potential for treating solid tumours, as well as for preventing clogged arteries and treating the autoimmune condition lupus.

In this latest study, Semir Beyaz at Cold Spring Harbor Laboratory in New York state and his colleagues wondered about the therapy’s potential for restoring function in an ageing intestine. They wanted to target senescent cells. These cells, which accumulate with age, have lost their ability to divide but remain metabolically active, releasing chemicals that promote inflammation and accelerate further ageing. To get to them, the team targeted a protein called uPAR, which is enriched on the surface of senescent cells.

“The decline we see in the ageing gut is a deficit in the fitness of the stem cells that renew the inner lining of the gut every three to five days,” says Beyaz. “We hypothesised that removal of the ‘unfit’ senescent cells would boost the regenerative capacity and fitness of the stem cells in old mice.”

To test this idea, the researchers engineered CAR T-cells in older mice to recognise uPAR on senescent cells and remove them. After the engineered cells were infused back into the mice, they observed that this restored the activity and number of their stem cells that maintain tissue function to levels that resemble younger mice. It also improved markers of gut barrier integrity and inflammation in these older mice to a greater extent than in another group of older mice that received CAR T-cell therapy that didn’t specifically target uPAR.

“When we removed these [senescent] cells using engineered CAR T-cells, we didn’t just stop the ageing process, but also observed a reversal, where the tissue began behaving similarly to that of younger mice,” says team member Corina Amor, also at Cold Spring Harbor Laboratory.

“This may eventually enable the amelioration of ageing-associated degradation of intestinal function, which may reduce susceptibility to diseases such as intestinal infections, deterioration of the structural integrity of the intestine, and even cancer,” says Tuomas Tammela at Memorial Sloan Kettering Cancer Center in New York, who wasn’t involved in the study. But he adds that researchers need to demonstrate that this approach is also effective and safe in people.

Team member Onur Eskiocak, also at Cold Spring Harbor Laboratory, says it is particularly important to uncover the optimal “dose” of the therapy before it can be trialled in people. “While uPAR is highly enriched on senescent unfit cells, low-level uPAR expression also may exist on normal tissues in other conditions,” he says.

Senescent cells also aren’t always bad news – they have been linked to tumour suppression and wound healing. “There’s no reporting [by the researchers] of what happens in other tissues where uPAR-positive are depleted,” says Jesse Poganik at Harvard Medical School.

We also don’t generally treat ageing by itself in an otherwise healthy person. What’s more, CAR-T therapy is expensive and logistically demanding to carry out. This – along with lingering safety concerns – means the approach probably won’t be widely rolled out for an indication like reversing the effects of ageing any time soon, says Joana Neves at King’s College London’s Centre. “For preventive or quality-of-life indications, the safety bar is higher than in oncology.”

But Beyaz maintains that reversing the decline of gut function in ageing has been a long-standing quest, particularly because, he says, there are no effective treatments to maintain gut barrier health when its regenerative capacity is compromised. This study is a step in the right direction, demonstrating that we can restore this vital function by removing the unfit cells that contribute to ageing, he says.