“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.”

BUFFALO, NY — July 27, 2026 — A new research paper was published in Volume 18 of Aging on July 13, 2026, titled “Slowing intervertebral disc aging in mice through long-term systemic treatment with the senolytic BCL-2/BCL-xL proteolysis targeting chimera (PROTAC) 753b.”

The study was led by first author Peter G. Alexander from the Ferguson Laboratory for Spine Research, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, and corresponding author Nam Viet Vo from the same institution. 

Intervertebral disc degeneration is a leading cause of chronic low back pain and disability. As discs age, they lose important structural components, become less able to absorb mechanical stress, and accumulate senescent cells—dysfunctional cells that stop dividing but continue releasing inflammatory molecules that contribute to tissue degeneration. Senolytic therapies, which selectively eliminate these cells, have emerged as a promising strategy to slow age-related diseases. In this study, researchers evaluated PROTAC 753b, a next-generation senolytic designed to target the anti-apoptotic proteins BCL-2 and BCL-xL while reducing the platelet toxicity associated with earlier drugs in this class.

The researchers treated 16-month-old male and female mice with PROTAC 753b for six months and evaluated their intervertebral discs at 22 months of age using histology, molecular analyses, and measurements of inflammatory markers. The treatment significantly improved several measures of intervertebral disc health in aged male mice, preserving the extracellular matrix protein aggrecan and reducing matrix metalloproteinase (MMP)-mediated aggrecan breakdown, a hallmark of disc degeneration. In contrast, female mice showed little overall improvement, revealing a sex-specific response to treatment.

To better understand how PROTAC 753b produced these benefits, the investigators examined markers of cellular senescence within the discs. However, treatment did not reduce expression of key senescence markers or significantly alter the drug’s molecular targets within disc tissue. Instead, treated male mice exhibited lower circulating levels of inflammatory proteins such as IL-6 and TNFα, suggesting that the therapy improved disc health primarily by reducing the systemic burden of senescent cells and inflammation rather than directly eliminating senescent cells within the intervertebral discs themselves.

The researchers also investigated why only male mice responded to treatment. Male mice developed substantially greater age-related disc degeneration than females, providing more opportunity for therapeutic improvement. Because female mice do not undergo menopause in the same way humans do, they may accumulate fewer senescent disc cells at this stage of aging. The authors suggest that these biological differences may contribute to the observed sex-specific response, although additional studies are needed to clarify the underlying mechanisms.

“These findings suggest that the BCL-2/BCL-xL targeting PROTAC 753b can ameliorate age-related IDD, representing a viable therapy strategy for mitigating IDD associated with aging.”

The study also highlights the complexity of treating age-related degeneration in tissues with limited blood supply. Although the investigators could not determine whether sufficient amounts of PROTAC 753b directly entered the largely avascular intervertebral discs, the findings suggest that lowering systemic senescence-associated inflammation alone may help preserve disc structure. This supports growing evidence that age-related degeneration is influenced not only by local tissue changes but also by broader biological processes occurring throughout the body.

Overall, the findings demonstrate that long-term systemic treatment with the senolytic PROTAC 753b slowed several features of age-related intervertebral disc degeneration in male mice. While further studies are needed to better understand its mechanisms and evaluate its potential in humans, the work provides new evidence that targeting cellular senescence may represent a promising strategy for slowing spinal disc degeneration associated with aging.

Paper DOI: https://doi.org/10.18632/aging.206394                        

Corresponding author: Nam Viet Vo – [email protected]          

Keywords: intervertebral disc aging, cellular senescence, senolytic, anti-apoptosis, PROTAC-753b

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