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

Article · Amor C, Fernández-Maestre I, Chowdhury S, Ho YJ, Nadella S, Graham C, Carrasco SE, Nnuji-John E, Feucht J, Hinterleitner C, Barthet VJA, Boyer JA, Mezzadra R, Wereski MG, Tuveson DA, Levine RL, Jones LW, Sadelain M, Lowe SW

- Archive id: doi:10.1038/s43587-023-00560-5
- Published: 2024-01-24
- Venue: Nature aging
- DOI: https://doi.org/10.1038/s43587-023-00560-5
- PMID: 38267706
- PMCID: PMC10950785
- Citations: 200
- Source URL: https://doi.org/10.1038/s43587-023-00560-5
- PDF: https://europepmc.org/articles/PMC10950785/pdf
- Provenance: europepmc

## 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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Biology of Aging & Longevity](https://space-kitty.com/topics/aging-longevity)

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