Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction
医学
内科学
作者
Corina Amor,Inés Fernández-Maestre,Saria Chowdhury,Yu-Jui Ho,Sandeep Nadella,Courtenay Graham,Sebastian E. Carrasco,Emmanuella Nnuji-John,Judith Feucht,Clemens Hinterleitner,Valentin J.A. Barthet,Jacob A. Boyer,Riccardo Mezzadra,Matthew G. Wereski,David A. Tuveson,Ross L. Levine,Lee W. Jones,Michel Sadelain,Scott W. Lowe
Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.