CAR-T Cell Therapy: A Natural Approach to Revitalizing Aging Intestinal Health

As we age, the cells that line our intestines gradually lose their ability to regenerate, impacting our immune health. However, recent research has successfully reversed this decline in older mice using genetically modified immune cells.

This innovative approach, known as CAR T-cell therapy, is primarily used to target specific blood cancers. It entails collecting a patient’s T cells, reprogramming them in a laboratory to identify and eliminate cancerous cells, and then reintroducing them into the bloodstream. Emerging variations of this therapy show promise not only in combatting solid tumors but also in preventing arterial blockages and treating autoimmune diseases like lupus.

In a groundbreaking study, Cemil Beyaz and his team at Cold Spring Harbor Laboratory, New York, explored the application of this therapy for revitalizing the aging gut. They focused on targeting damaged cells, known as senescent cells, which accumulate over time, fail to proliferate, and secrete substances that exacerbate inflammation and promote further aging. The researchers aimed their intervention at a protein called uPAR, prevalent on aging cells.

“The decline in gut health we observe with aging is linked to diminished stem cell fitness responsible for renewing the intestinal lining every three to five days,” Beyaz states. “We posited that eliminating these ‘unfit’ senescent cells would enhance the regenerative ability and overall functionality of stem cells in older mice.”

To validate this hypothesis, the researchers engineered CAR T cells from older mice to specifically recognize and eliminate uPAR on senescent cells. Upon reintroducing these modified cells, the researchers noted a significant increase in both the activity and number of stem cells maintaining tissue function, reaching levels comparable to those observed in younger mice. The treated older mice also exhibited marked improvements in intestinal barrier integrity and reduced inflammation compared to a separate cohort that received CAR T-cell therapy targeting different mechanisms.

“By removing senescent cells, we not only inhibited the aging process but also witnessed a reversal, with tissues displaying characteristics similar to those of young mice,” said team member Corina Amor, also from Cold Spring Harbor Laboratory.

“This therapy could potentially reverse age-related declines in bowel function, decreasing vulnerability to diseases such as intestinal infections, compromised intestinal integrity, and even cancer,” explained Tuomas Tammera from Memorial Sloan Kettering Cancer Center, who was not part of the study. However, he emphasized that ensuring the treatment’s effectiveness and safety in humans remains crucial.

Onur Eskiokaku, a researcher at Cold Spring Harbor Laboratory, highlighted the importance of determining the optimal dosage before advancing to human trials. “While uPAR is abundant in aged, defective cells, it may also be present in healthy tissues under certain conditions,” he noted.

It’s important to remember that senescent cells aren’t all detrimental; they play roles in tumor suppression and wound healing. “We are investigating the implications of depleting uPAR expression in other tissues,” mentioned Jesse Poganic from Harvard Medical School.

Additionally, treating aging in otherwise healthy individuals is not commonplace. The complexity and expense associated with CAR-T therapy, coupled with ongoing safety concerns, suggest that widespread application for reversing aging effects is not imminent, according to Joanna Neves at the Center at King’s College London. “Safety standards for preventative treatments must be more stringent than those for oncology.”

Beyaz asserts that addressing the age-related decline in intestinal function has long posed a challenge, with no effective solutions currently available, especially when the intestinal barrier’s regenerative capability is compromised. This research marks a significant step forward, indicating that the removal of unfit cells can restore crucial functions.