Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction Journal Article
| 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. |
| Article Title: | Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction |
| 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. © The Author(s) 2024.; The accumulation of senescent cells drives age-related diseases. In this study, the authors show that senolytic CAR T cells can rejuvenate metabolic function and fitness in old mice and that a single dose is sufficient to lead to long-term preventive effects. © The Author(s) 2024. |
| Keywords: | controlled study; protein expression; drug efficacy; nonhuman; flow cytometry; t lymphocyte; mouse; animal tissue; gene expression; animal experiment; exercise; histology; age; genetic transduction; blood sampling; prophylaxis; cell isolation; plasmid; insulin; glucose blood level; metabolic syndrome x; fluorescence activated cell sorting; cell aging; glucose tolerance test; male; female; article; immunofluorescence assay; differential expression analysis; differential gene expression; single cell rna seq; pathway enrichment analysis; hepatic stellate cell; recombinant human insulin; insulin tolerance test |
| Journal Title: | Nature Aging |
| Volume: | 4 |
| Issue: | 3 |
| ISSN: | 2662-8465 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-01 |
| Start Page: | 336 |
| End Page: | 349 |
| Language: | English |
| DOI: | 10.1038/s43587-023-00560-5 |
| PROVIDER: | scopus |
| PMCID: | PMC10950785 |
| PUBMED: | 38267706 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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