Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients' treatment

Abstract

The involvement of cellular senescence in the initiation and propagation of diseases is clearly characterized, making the elimination of senescent cells essential to treat age-related diseases. The development of senolytic drugs demonstrated that targeting these cells limits the deterioration of patients' condition, by inducing apoptosis. Nevertheless, the first generations of senolytics which has been developed displayed their activities through specific mechanisms and demonstrated several limitations during clinical development. However, the rational to eliminate senescent cells remains evident, with the necessity to develop specific therapies in a context of diseases and tissues. The evolutions in the field of drug discovery open the way to a new generation of senolytic therapies, such as immunological approaches (CAR-T cells, Antibody-Drug Conjugated or vaccines), which require preliminary steps of research to identify markers specifically expressed on senescent cells, demonstrating promising specific effects. Currently, the preclinical development of these strategies appears more challenging to avoid strong side effects, but the expected results are commensurate with patients' hopes for treatments. In this review, we highlight the fact that the classical senolytic approach based on drug repurposing display limited efficacy and probably reached its limits in term of clinical development. The recent development of more complex therapies and the extension of interest in the domain of senescence in different fields of research allow to extend the possibility to discover powerful therapies. The future of age-related diseases treatment is linked to the development of new approaches based on cell therapy or immunotherapy to offer the best treatment for patients.

Fig. 1. Overview of therapies to eliminate senescent cells.

Senolytic approach is based on the expression of specific markers expressed in the cytoplasm or at the plasma membrane of senescent cells. Several therapies have been developed such as pharmacological inhibitors and antibody-drug conjugated or CAR-T cells and display different mechanisms of actions. Created with BioRender.com.

Fig. 2. Vaccine and immunological approaches used to target specifically senescent cells.

Activation or modulation of the immune system trigger the recognition and the elimination of senescent cells. Created with BioRender.com.