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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction
Corina Amor1, Inés Fernández-Maestre2,3, Saria Chowdhury4
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. amor@cshl.edu.
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.
Insights
Senescent cells drive aging decline. New CAR T-cell therapy targeting uPAR safely clears these cells, improving physical fitness and metabolic function in aged mice with lasting effects from a single dose.
Area of Science:
- Gerontology
- Immunotherapy
- Cellular senescence
Background:
- Senescent cells accumulate with age, contributing to tissue dysfunction and age-related diseases.
- Existing senolytic drugs require continuous administration and have limitations.
- Chimeric antigen receptor (CAR) T cells offer a targeted approach to eliminate senescent cells.
Purpose of the Study:
- To investigate the efficacy of senolytic CAR T cells targeting urokinase plasminogen activator receptor (uPAR) in aging.
- To evaluate the therapeutic potential of anti-uPAR CAR T cells in ameliorating age-related pathologies.
Main Methods:
- Development of CAR T cells targeting the senescence-associated protein uPAR.
- Administration of anti-uPAR CAR T cells to aged mice and mice on a high-fat diet.
- Assessment of exercise capacity, glucose tolerance, and metabolic function post-treatment.
Main Results:
- uPAR-positive senescent cells were found to accumulate during aging.
- A single administration of anti-uPAR CAR T cells safely targeted and eliminated senescent cells.
- Treatment improved exercise capacity and ameliorated metabolic dysfunction, including glucose intolerance.
- Therapeutic and preventive effects were long-lasting following a single treatment.
Conclusions:
- Senolytic CAR T cells targeting uPAR represent a promising therapeutic strategy for age-related decline.
- A single administration of this therapy can achieve sustained improvements in physiological aging and metabolic health.
- This approach offers a potential alternative to continuous drug administration for senolytic therapy.
