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Research Paper|Volume 18|pp 833—853

Slowing intervertebral disc aging in mice through long-term systemic treatment with the senolytic BCL-2/BCL-xL proteolysis targeting chimera (PROTAC) 753b

Peter G. Alexander1, Bowen Yan2, Karen L. Clark1, Qing Dong1, Dong Wang1, Yang Yang2,3, Ting Zhang1, Peiyi Zhang4, Guangrong Zheng4, Paul D. Robbins5, Gwendolyn A. Sowa1,6, Joon Y. Lee1, Daohong Zhou2,3, Nam Viet Vo1
  • 1Ferguson Laboratory for Spine Research, Department of Orthopaedic Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
  • 2The Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
  • 3The Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
  • 4Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
  • 5Masonic Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA
  • 6The Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Received: October 27, 2025Accepted: May 15, 2026Published: July 13, 2026
https://doi.org/10.18632/aging.206394

Copyright: © 2026 Alexander et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The senolytic PROTAC (753b) eliminates senescent cells (SnCs) by targeting ubiquitin-mediated destruction of the anti-apoptotic BCL-2/BCL-xL proteins. Here, systemic treatment with 753b was tested for reduction of age-related intervertebral disc degeneration (IDD) in mice. Five aging male and female mice were intraperitoneally injected with 753b or vehicle between 16 and 22 months of age. Among vehicle controls, intervertebral disc (IVD) histology using Safranin-O/Fast Green staining of paraffin embedded transverse sections revealed significantly greater IDD in 22m old males than age-matched females. In 22-month-old males, 753b treatment significantly reduced matrix metalloproteinase (MMP)-mediated aggrecan proteolysis as shown by Western blots, loss of disc matrix aggrecan by immunohistochemistry, age-related histomorphologic features of IDD, and serum protein levels of IL-6 and TNFα protein in treated male mice. While expression of IVD cellular senescence markers IL-6, IL-8, TNFα and p16INK4a assessed by RT-PCR of IVD tissue increased with age in both 22m old female and male mice, expression of these markers was not reduced by 753b treatment. These results demonstrate that 753b treatment of aging mice reduced IDD in males but not females, which suggests sex-based differences in the role of senescence in IDD and may have an impact on the potential for females to benefit from anti-senescent therapies for IDD. The observed therapeutic effects of 753b on IVDs of the male mice suggest a global reduction of cellular senescence burden through systemic, non-cell autonomous processes.