Targeting senescent cells with dasatinib quercetin preserves disc architecture and modulates degeneration-related pathways in a mouse model.
Disc degeneration is a major cause of chronic back and neck pain, but current treatments primarily focus on relieving symptoms rather than preventing disease progression. There is increasing evidence that cellular senescence, in which cells lose their ability to proliferate and secrete inflammatory factors, plays a central role in accelerating the destruction of intervertebral disc tissue. However, it is still not fully understood how genetic susceptibility influences early onset of disease and whether treatments targeting aging can change this trajectory.
To address this challenge, a research team led by Makarand V. Risbad, the James J. Maguire Jr. Professor of Orthopedic Surgery at Thomas Jefferson University’s Sidney Kimmel School of Medicine, investigated whether senolytic therapy could slow 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 the combination of dasatinib and quercetin (DQ), a widely studied senolytic cocktail. Their findings were published in Volume 14 of the journal on April 14, 2026. bone research.
The research team used histological, molecular, imaging, and transcriptomic analyzes to systematically assess structural, cellular, and molecular changes in the intervertebral disc over time. They found that SM/J mice showed elevated aging markers as early as 4 weeks of age, prior to obvious structural degeneration. This early aging burden was accompanied by inflammatory activation and changes in gene expression associated with stress and extracellular matrix remodeling.
“Importantly, early molecular changes occur prior to visible tissue damage, suggesting that aging is not simply a result of degeneration, but rather a driver of genetically susceptible discs.” explained Professor Lisbad.
Treatment with dasatinib quercetin significantly reduced the severity of disc degeneration compared to untreated controls. Mice treated with DQ showed improved preservation of nucleus pulposus architecture, reduced degenerative remodeling, decreased expression of aging markers such as p19ARF and p21, and decreased inflammatory signaling. Importantly, these benefits were not observed to the same extent with navitoclax, which failed to improve molecular or structural outcomes.
More detailed transcriptome analysis revealed that DQ treatment reestablished gene expression programs related to inflammation, stress response, and cell cycle control, consistent with reduced aging and improved tissue homeostasis. Further computational and functional analyzes implicated JNK (c-Jun N-terminal kinase) signaling as a central pathway associated with disease progression and treatment response.
“These data demonstrate that JUN signaling is a convergent hub linking aging, inflammation, and extracellular matrix destruction and help explain why pathway-specific modulation with dasatinib-quercetin is effective.”” pointed out Professor Risbad.
Functional experiments using human degenerating disc cells confirmed these findings. Inhibition of JUN signaling recapitulated the important effects of DQ treatment, reducing aging-associated β-galactosidase activity and reducing inflammatory gene expression. These results suggest that JUN signaling may function as a regulatory hub linking disc aging, inflammation, and tissue degeneration.
Beyond mechanistic insights, this study highlights broader implications for musculoskeletal aging and regenerative medicine. In the short term, these findings improve our understanding of how genetic susceptibility interacts with cellular senescence to cause early disc degeneration. In the long term, it may help develop targeted aging treatment strategies aimed at slowing disease progression in at-risk individuals before irreversible tissue damage occurs.
This study also highlights that senolytic efficacy is highly context-dependent, with different agents producing different results depending on tissue type and underlying molecular pathways. This has implications for future treatment design, potentially shifting focus to pathway-specific interventions rather than broad senescent cell ablation.
Overall, this study provides preclinical evidence that dasatinib quercetin can slow early disc degeneration by suppressing aging-related pathways, preserving disc structure, and reducing inflammation and fibrotic tissue changes, and JUN signaling emerges as a potential therapeutic target.
sauce:
thomas jefferson university
Reference magazines:
Novais, E.J. Others. (2026). Senenolytic treatment of dasatinib and quercetin slows early-onset disc degeneration in SM/J mice. Bone research. DOI: 10.1038/s41413-026-00526-4. https://www.nature.com/articles/s41413-026-00526-4
