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Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction
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Abstract
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.
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A single dose of uPAR-targeted CAR T-cells reversed liver fibrosis, restored intestinal stem cell function, and conferred long-term metabolic benefits in aged mice.
“a single dose of uPAR-targeted CAR T-cells was sufficient to reverse liver fibrosis, restore intestinal stem cell function, and confer long-term metabolic benefits in aged mice65.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [65]
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Cited by
Sorted by citations
Targeting aging and age-related diseases with vaccines
Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G.-H. (2024) · Nature Aging · doi:10.1038/s43587-024-00597-0 · Cited by 66
Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming
Zhang, W., Song, S., Zhang, Y., Pan, Y., Hu, D., & Wang, Y. (2026) · npj Aging · doi:10.1038/s41514-026-00355-z · Cited by 6
Metadata
- Authors
- Amor, C., Fernández-Maestre, I., Chowdhury, S., Ho, Y.-J., Nadella, S., Graham, C., Carrasco, S. E., Nnuji-John, E., Feucht, J., Hinterleitner, C., Barthet, V. J. A., Boyer, J. A., Mezzadra, R., Wereski, M. G., Tuveson, D. A., Levine, R. L., Jones, L. W., Sadelain, M., & Lowe, S. W.
- Venue
- Nature Aging
- Published
- 2024-01-24
- Volume
- 4
- Issue
- 3
- Pages
- 336-349
- ISSN
- 2662-8465
- PMC
- PMC10950785
- Cited by
- 228
- References
- 20
- Language
- en
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