Senolytic therapy delays early disc degeneration in mouse model

Targeting senescent cells with dasatinib-quercetin preserves disc structure and modulates degeneration-associated pathways in a mouse model.

Intervertebral disc degeneration is a major cause of chronic back and neck pain, yet current treatments largely focus on symptom relief rather than preventing disease progression. A growing body of evidence suggests that cellular senescence, where cells lose proliferative capacity and secrete inflammatory factors, plays a central role in accelerating disc tissue breakdown. However, how genetic susceptibility influences early disease onset and whether senescence-targeting therapies can alter this trajectory has remained poorly understood.

To address this challenge, a research team led by the James J. Maguire Jr. Professor Makarand V. Risbud from the Department of Orthopaedic Surgery at Sidney Kimmel Medical College, Thomas Jefferson University, USA, investigated whether senolytic therapies could delay degeneration in SM/J mice, a model of spontaneous early-onset disc disease. The researchers compared two approaches: navitoclax, which targets BCL-2 family survival proteins, and a combination of dasatinib and quercetin (DQ), a widely studied senolytic cocktail. Their findings were published on April 14, 2026, in Volume 14 of the journal Bone Research.

Using histological, molecular, imaging, and transcriptomic analyses, the team systematically evaluated structural, cellular, and molecular changes in intervertebral discs over time. They found that SM/J mice exhibited elevated senescence markers as early as four weeks of age, preceding overt structural degeneration. This early senescence burden was accompanied by inflammatory activation and gene expression changes linked to stress and extracellular matrix remodeling.

"Importantly, early molecular changes preceded visible tissue damage, suggesting that senescence is not just a consequence of degeneration but a driving force in genetically susceptible discs," explained Prof. Risbud.

Treatment with dasatinib-quercetin significantly reduced disc degeneration severity compared with untreated controls. Mice receiving DQ showed improved preservation of nucleus pulposus structure, reduced degenerative remodeling, lower expression of senescence markers such as p19^ARF and p21, and decreased inflammatory signaling. Importantly, these benefits were not observed to the same extent with navitoclax, which failed to improve either molecular or structural outcomes.

A deeper transcriptomic analysis revealed that DQ treatment reshaped gene expression programs related to inflammation, stress responses, and cell cycle regulation, consistent with reduced senescence and improved tissue homeostasis. Further computational and functional analyses implicated JNK (c-Jun N-terminal kinase) signaling as a central pathway associated with disease progression and therapeutic response.

"These data point to JUN signaling as a convergence hub linking senescence, inflammation, and extracellular matrix breakdown, helping explain why pathway-specific modulation by dasatinib-quercetin is effective," Prof. Risbud noted.

Functional experiments using human degenerated disc cells supported these findings. Inhibition of JUN signaling recapitulated key effects of DQ treatment, reducing senescence-associated β-galactosidase activity and lowering inflammatory gene expression. These results suggest that JUN signaling may act as a regulatory hub connecting senescence, inflammation, and tissue degeneration in the intervertebral disc.

Beyond mechanistic insights, the study highlights broader implications for musculoskeletal aging and regenerative medicine. In the short term, these findings improve understanding of how genetic susceptibility interacts with cellular senescence to drive early disc degeneration. In the longer term, they may guide development of targeted senotherapeutic strategies aimed at slowing disease progression in at-risk individuals before irreversible tissue damage occurs.

The research also underscores that senolytic efficacy is highly context-dependent, with different drugs producing distinct outcomes depending on tissue type and underlying molecular pathways. This could influence future therapeutic design, shifting attention toward pathway-specific interventions rather than broad senescent cell elimination.

Overall, the study provides preclinical evidence that dasatinib-quercetin can delay early disc degeneration by suppressing senescence-associated pathways, preserving disc structure, and reducing inflammation and fibrotic tissue changes, with JUN signaling emerging as a potential therapeutic target.