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The Proteasome02:18

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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Proteolysis targeting chimeras as senolytics: An emerging senotherapy for combating aging.

Alexis B Cruickshank-Taylor1, Jacob S Kozora1, Jennifer S Carew2

  • 1Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.

The Journal of Pharmacology and Experimental Therapeutics
|November 9, 2025
PubMed
Summary

Senolytics clear senescent cells to combat aging but have toxicities. Proteolysis targeting chimeras (PROTACs) offer a safer, more effective senolytic strategy by degrading target proteins, improving healthspan.

Keywords:
AgingPROteolysis TArgeting ChimerasProdrugSenescent cellsSenolytics

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Area of Science:

  • Gerontology and Molecular Biology
  • Drug Discovery and Development

Background:

  • Cellular senescence contributes to aging and tissue dysfunction.
  • Current senolytics, often repurposed anticancer drugs, exhibit toxicities limiting their use in the elderly.
  • Senescent cell clearance improves healthspan and tissue repair.

Purpose of the Study:

  • To review the development of Proteolysis Targeting Chimeras (PROTACs) as senolytics (SenoTACs).
  • To highlight the advantages of SenoTACs over traditional senolytics for treating aging-related diseases.
  • To address the unmet need for safer and more effective anti-aging therapies.

Main Methods:

  • Review of recent literature on senescence-targeting PROTACs.
  • Comparison of SenoTACs with small molecule senolytics.
  • Analysis of safety and efficacy profiles of emerging SenoTACs.

Main Results:

  • SenoTACs selectively eliminate senescent cells via targeted protein degradation.
  • SenoTACs demonstrate improved safety and efficacy compared to small molecule senolytics.
  • Examples of developed SenoTACs include ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99.

Conclusions:

  • SenoTACs represent a promising therapeutic strategy for aging-related diseases.
  • The substoichiometric degradation mechanism of SenoTACs offers enhanced efficacy and reduced resistance.
  • SenoTACs have the potential to overcome the toxicity limitations of current senolytics.