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Annual Review of Pharmacology and Toxicology

Volume 61, 2021

Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span

Abstract

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.

Keyword(s): aging, senescence, senescence-associated secretory phenotype, senolytics, senomorphics
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2021-01-06
2025-04-28
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/content/journals/10.1146/annurev-pharmtox-050120-105018
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Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Annual Review of Pharmacology and Toxicology 61, 779 (2021); https://doi.org/10.1146/annurev-pharmtox-050120-105018
/content/journals/10.1146/annurev-pharmtox-050120-105018
/content/journals/10.1146/annurev-pharmtox-050120-105018
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Supplementary Data

  • Download the Supplemental Appendix (PDF).

    Supplemental Figure 1. Schematic of the INK-ATTAC (A) and p16-3MR (B) mice. (A) The INK-ATTAC mice express a caspase 8-FKBP fusion protein from a p16Ink4a promoter fragment. This drives apoptosis of p16Ink4a expressing cells in vivo after administration of the drug AP20187, which promotes dimerization of FKBP and thereby caspase 8. (B) p16-3MR mice express a fusion of three transgenic reporters, the renilla luciferase (LUC), monomeric red fluorescent protein (mRFP), and herpes simplex virus 1 thymidine kinase (HSV-TK) under the control of a p16Ink4a promoter in a BAC construct, allowing for specific killing of p16Ink4a expressing cells when the drug ganciclovir (GCV) is administered to mice. GCV is by converted by HSV-TK. to GCV-triphosphate, which is a toxic chain terminator of DNA replication. (Figure courtesy of Dr. Carolina Soto Palma.) (Download Supplemental Figure 1 as a PDF.)

  • Article Type: Review Article

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