Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Abstract

<title>Abstract</title> Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline^1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness^3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis⁸. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.