Senolytic CAR T cells reverse senescence-associated pathologies
Open accessAbstract
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8–10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases. Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.
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Certain cell surface proteins are more highly expressed by senescent cells than most other cell types, prompting development of CAR T cells, vaccines, and antibody-drug conjugates targeting these markers.
“Certain cell surface proteins tend to be more highly expressed by senescent cells than most other cell types, which prompted development of engineered chimeric antigen receptor (CAR) T cells, vaccines and antibody–drug conjugates targeting these cell surface markers.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [96]
The paper’s Abstract reports that surface proteins are upregulated in senescent cells and that the authors developed uPAR-targeting CAR T cells. It does not report the development of vaccines or antibody–drug conjugates targeting those markers, so those parts of the attributed claim are unsupported. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThese immune-targeting approaches eliminate senescent cells, but in some cases also affect activated macrophages and other non-senescent cell types.
“Each of these approaches eliminates senescent cells, although in some cases, activated macrophages and other non-senescent cell types are also affected96–99.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [96]
The paper reports that uPAR-directed CAR T cells eliminate senescent cells and that supratherapeutic doses cause macrophage accumulation and activation (Abstract, page unavailable). It also notes uPAR expression in monocytes, macrophages, neutrophils and bronchial epithelium, but does not show that those naturally occurring non-senescent cells were eliminated or otherwise affected by treatment. Its killing experiment used non-senescent leukemia cells engineered to express uPAR. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAnti-uPAR-CAR-T cells were effective in removing senescent cells in vitro and pre-cancerous and malignant cells in mouse models of liver and lung.
“It was found that anti-uPAR-CAR-T cells were effective in removing senescent cells in vitro and pre-cancerous and malignant cells in mouse models of liver and lung in the presence of potentially toxic.350”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [350]
The paper reports that uPAR CAR T cells eliminated senescent cells in vitro, reduced senescent hepatocytes in mice, and decreased senescent tumor cells in a mouse lung adenocarcinoma model (Abstract; pages unavailable). It describes the liver cells as oncogene-induced senescent hepatocytes, not explicitly as pre-cancerous cells, so that characterization is not established by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMice with lung adenocarcinomas exposed first to MEK and CDK4/6 inhibitors to induce senescence and then to uPAR-targeting CAR T cells to selectively kill senescent cells showed a marked delay in tumour growth.
“Mice with lung adenocarcinomas were first exposed to a combination of MEK and CDK4/6 inhibitors to induce senescence, and then received uPAR- targeting CAR Tcells to selectively kill those senescent cells, leading to a marked delay in tumour growth 22 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [22]
The paper’s lung adenocarcinoma passage describes MEK and CDK4/6 inhibitor treatment followed by uPAR-targeted CAR T cells, and reports fewer senescent tumour cells and significantly prolonged survival. Extended Data Fig. 5 describes a survival analysis, not a measurement of tumour growth, so the claimed marked delay in tumour growth is not established by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRecent work has shown that senolytic CAR T cell therapy can reduce senescence-associated diseases.
“Exciting recent work has demonstrated that senolytic CAR T cell therapy can attenuate senescence-associated diseases226.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [226]
PLAUR (uPAR) is associated with extracellular remodeling and increased secretion by senescent cells.
“and PLAUR (uPAR) is associated with extracellular remodeling and increased secretion by senescent cells (Amor et al, 2020).”
From Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues (2025) · cites this paper as Amor et al, 2020
Amor et al. engineered CAR T cells recognizing uPAR, a protein expressed by senescent cells, a strategy that mirrors normal senescence immunosurveillance.
“Amor et al. (2020) engineered chimeric antigen receptor (CAR) T cells recognizing uPAR, a protein expressed by senescent cells, a strategy that mirrors normal senescence immunosurveillance.”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Amor et al. 2020
These "senolytic CAR T cells" can be used not just as an anticancer therapy, but to treat other senescence-associated disorders, such as nonalcoholic steatohepatitis (NASH).
“these “senolytic CAR T cells” can be used not just as an anticancer therapy, but to treat other senescence-associated disorders, such as nonalcoholic steatohepatitis (NASH) (Amor et al. 2020).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Amor et al. 2020
Other plasma membrane proteins whose expression has been reported to change during senescence are receptor-type tyrosine protein phosphatase DEP-1, β2-microglobulin, membrane-bound oxidized vimentin, dipeptidyl peptidase 4 and urokinase-type plasminogen activator receptor (uPAR).
“Other plasma membrane proteins whose expression has also been reported to change during senescence are receptor- type tyrosine protein phosphatase DEP-1, β 2 -microglobulin, membrane- bound oxidized vimentin, dipeptidyl peptidase 4 and urokinase- type plasminogen activator receptor (uPAR) 22,61,62 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [22]
CAR T cells targeting uPAR on the surface of senescent cells have been developed as promising cell-based senolytics.
“Moreover, CAR Tcells targeting uPAR on the surface of senescent cells have been developed as promising cell- based senolytics 22 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [22]
CAR-T cells targeting the senescent cell-specific surface molecule uPA receptor are effective senolytic drugs.
“chimeric antigen receptor redirected T (CAR-T) cells that target the senescent cell-specific surface molecule uPA receptor [116]”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [116]
CXCL16 is upregulated in aging and inflammatory conditions linked to senescence.
“Additionally, CXCL16 is upregulated in aging and inflammatory conditions linked to senescence”
From Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues (2025) · cites this paper as Amor et al, 2020
The paper’s main text reports increased uPAR in senescent-cell models, not CXCL16. Searches for “CXCL16” and for its upregulation in aging and inflammatory conditions found no passage addressing the claim in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredTransplantation of a small proportion of senescent cells or injection of CAR T cells with a senescent phenotype accelerated physical dysfunction and reduced lifespan in mice.
“transplantation of a small proportion of senescent cells or injection of chimeric antigen receptor (CAR) Tcells with a senescent phenotype accelerated physical dysfunction and reduced lifespan 21,22”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [22]
The paper describes CAR T cells designed to eliminate senescent cells, not CAR T cells with a senescent phenotype. Its treatment passage reports that mice given an effective dose remained active, but does not address whether injecting senescent CAR T cells or transplanting a small proportion of senescent cells accelerates dysfunction or reduces lifespan. Searches for those interventions and outcomes found no passage establishing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCAR-T depletion of only HSCs expressing the senescence marker uPAR improved inflammation and fibrosis.
“This approach was successfully validated by a study that used CAR-T to deplete only HSCs that expressed the senescence marker urokinase plasminogen activator receptor (uPAR), thereby improving inflammation and fibrosis (128).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [128]
In mouse models, CAR T cells directed against uPAR reduce experimental liver fibrosis.
“In mouse models, CAR T cells directed against uPAR (urokinase-type plasminogen activator receptor), which is abundantly present on senescent cells, ameliorates experimental liver fibrosis.146”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [146]
uPAR-specific CAR-T cells can effectively eliminate senescent cells in vitro and in vivo and prolong the survival of lung adenocarcinoma mice.
“Moreover, recent studies have shown that uPAR-specific CAR-T cells can effectively eliminate senescent cells in vitro and in vivo and prolong the survival of lung adenocarcinoma mice [127].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [127]
Senescence markers beyond p16 include p21, p19, uPAR, and GPNMB.
“Studies have begun to reveal the remarkable heterogeneity of cellular senescence in different tissues, highlighting the importance of cellular senescence markers beyond p16 – including Cdkn1a (p21) [7–10], Cdkn2d (p19) [11], uPAR [12], and glycoprotein non-metastatic melanoma protein B (GPNMB) [13] – and emphasizing the urgent need for a better understanding of senescent cell heterogeneity.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [12]
uPAR was identified as a unique senescence marker by comparing differentially expressed genes in bulk RNA-seq datasets of three known mouse models of senescence, and was validated by flow cytometry.
“In another study, urokinase plasminogen activator receptor (uPAR), was identified as a unique senescence marker by comparing differentially expressed genes in bulk RNA-seq datasets of three known mouse models of senescence, and was validated by flow cytometry [12].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [12]
Elimination of uPAR-expressing cells with CAR T cells specifically kills senescent cells both in vivo and in vitro, and extends the lifespan of mice with lung adenocarcinoma.
“Elimination of uPAR-expressing cells with chimeric antigen receptor (CAR) T cells specifically kills senescent cells both in vivo and in vitro, and extends the lifespan of mice with lung adenocarcinoma [12].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [12]
CAR T cells targeting uPAR effectively ablated senescent cells in vitro and in murine models of lung adenocarcinomas and liver fibrosis.
“Similarly, chimeric antigen receptor (CAR) T cells targeting the urokinase-type plasminogen activator receptor (uPAR), reported to be a specific cell surface marker in certain senescent cell populations, effectively ablated senescent cells in vitro and in murine models of lung adenocarcinomas and liver fibrosis (49).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [49]
The success of immunotherapies in different forms of cancer have also led to proof-of-concept studies for targeting senescent cells.
“The success of immunotherapies in different forms of cancer have also led to proof-of-concept studies for targeting senescent cells (Amor et al., 2020; Kim et al., 2017).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Amor et al., 2020
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Theranostic cells: emerging clinical applications of synthetic biology
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- Authors
- Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., Kulick, A., Houlihan, S., Peerschke, E., Friedman, S. L., Ponomarev, V., Piersigilli, A., Sadelain, M., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Sadelain, Michel
- Lowe, Scott W.
- ORCID
- Venue
- Nature
- Published
- 2020-06-17
- Volume
- 583
- Issue
- 7814
- Pages
- 127-132
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7583560
- OpenAlex
- W3036603151
- Semantic Scholar
- 04e18a651e78de49d44a74b1db3d968208b4c3a1
- Cited by
- 1,098
- References
- 60
- Citations by year
- 2026: 194 · 2025: 236 · 2024: 208 · 2023: 147 · 2022: 135 · 2021: 131 · 2020: 45 · 2012: 1
- FWCI
- 68.89
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-02-21)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (U54OD020355)
- National Institute on Aging (AG065396, R56AG016379, R01AG016379, R01AG065396)
- National Cancer Institute (P01CA129243, P30CA008748)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056621)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, chimeric antigen receptor T cells, urokinase-type plasminogen activator receptor, liver fibrosis, lung adenocarcinoma, senescence-associated secretory phenotype, tissue homeostasis
- MeSH terms
- Receptors, Chimeric Antigen, Adenocarcinoma, Aging, Animals, Carbon Tetrachloride, Female, Humans, Liver Cirrhosis, Longevity, Lung Neoplasms, Male, Receptors, Cell Surface, Rejuvenation, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Cellular Senescence, Mice, Receptors, Urokinase Plasminogen Activator, Heterografts
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