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

Amor, Corina, Fernández-Maestre, Inés, Chowdhury, Saria, Ho, Yu-Jui, Nadella, Sandeep, Graham, Courtenay, Carrasco, Sebastian E, Nnuji-John, Emmanuella, Feucht, Judith, Hinterleitner, Clemens, Barthet, Valentin JA, Boyer, Jacob A, Mezzadra, Riccardo, Wereski, Matthew G, Tuveson, David A, Levine, Ross L, Jones, Lee W, Sadelain, Michel, Lowe, Scott W (January 2024) Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nature Aging. ISSN 2662-8465 (Public Dataset)

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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.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:	Nadella, Sandeep Nnuji-John, Emmanuella Tuveson, David A. Lowe, Scott W. Amor, Corina Chowdhury, Saria
Communities:	CSHL Cancer Center Program CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Animal Shared Resource CSHL Cancer Center Shared Resources > Single-Cell Biology Service CSHL labs > Lowe lab CSHL labs > Tuveson lab CSHL labs > Amor lab School of Biological Sciences > Publications CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	24 January 2024
Date Deposited:	30 Jan 2024 19:28
Last Modified:	29 Apr 2024 18:22
Related URLs:	Publisher
Dataset ID:	GEO: GSE243616 https://twc-stanford.shinyapps.io/maca/ https:// zenodo.org/records/7311202#.Y20ybezMIyl/
URI:	https://repository.cshl.edu/id/eprint/41424

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