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 (September 2023) Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Research Square. (Submitted)

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Abstract

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline1,2. 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 fitness3-7. 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.

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 organism description > animal 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 organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:	Nadella, Sandeep Nnuji-John, Emmanuella Tuveson, David A. Amor, Corina Chowdhury, Saria
Communities:	CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Antibody and Phage Display Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL Cancer Center Shared Resources > Animal Shared Resource CSHL Cancer Center Shared Resources > Organoid Service CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service CSHL Cancer Center Shared Resources > Single-Cell Biology Service School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	26 September 2023
Date Deposited:	24 Oct 2023 13:12
Last Modified:	29 Feb 2024 18:05
PMCID:	PMC10571605
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41282

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