2026/02/11 by Peter Alexander, Bowen Yan, Karen Clark +11 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Multiple Myeloma Research and Treatments #Protein Degradation and Inhibitors #Spine and Intervertebral Disc Pathology
paper · pdf · doi:10.18632/aging.206394
openalex publication_date 2026/02/11 · openalex created_date 2026/07/14 · openalex updated_date 2026/07/22
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 agerelated 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 p16 INK4a 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 sexbased 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.