Senolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitness.

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature of the aging process, little is known about the in vivo effects of senescent cells on intestinal fitness. Here, we identify the accumulation of senescent cells in the aging gut and, by harnessing senolytic CAR T cells to eliminate them, we uncover their detrimental impact on epithelial integrity and overall intestinal homeostasis in natural aging, injury and colitis. Ablation of intestinal senescent cells with senolytic CAR T cells in vivo or in vitro is sufficient to promote the regenerative potential of aged ISCs. This intervention improves epithelial integrity and mucosal immune function. Overall, these results highlight the ability of senolytic CAR T cells to rejuvenate the intestinal niche and demonstrate the potential of targeted cell therapies to promote tissue regeneration in aging organisms.
Competing Interests: S.B. received research funding from Caper Labs, Elstar Therapeutics and Revitope Oncology for research unrelated to this study. S.B. is an advisor for Caper Labs. S.B and C.A. are listed as inventors on a patent application related to the regenerative effects of senolytic CAR T cells (63/510,997). M.S and C.A. are listed as the inventor of several patent applications (62/800,188; 63/174,277; 63/209,941; 63/209,940; 63/209,915; 63/209,924; 17/426,728; 3,128,368; 20748891.7; 2020216486) related to senolytic CAR T cells. M.S. is also listed on other unrelated patents concerning CAR T technology. M.S. and C.A. are advisors for Fate Therapeutics.