Abstract
Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.
Highlights
Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability
Supporting histological observations, the 18–23 M D + Q group presented grade distributions, as well as similar pooled and level-by-level average grades comparable to the Vehicle-treated control animals (Veh) group (Supplementary Fig. 1c, d). These results provide strong evidence that D + Q treatment mitigates age-related disc degeneration, a key intervention window exists, and the disease status at the start of the treatment is crucial for therapeutic success
To study the age-dependent progression of senescence-associated secretory phenotype (SASP) markers in the disc and whether they are responsive to D + Q, we evaluated the abundance of IL-1β, IL-6, and MMP13 (Fig. 2a–c”’), wellestablished SASP markers in different tissues, including the intervertebral disc[10,11,18,35]
Summary
Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. We analyzed AcanCreERT2;p16Ink4a conditional knockout mice and found decreased levels of cell death, SASP, and aberrant matrix changes in the discs of aged mice[11]. This finding is supported by reduced oxidative stress and disc degeneration in Cdkn2a germline knockout mice in response to a tail suspension injury model[14]. 7112 and o-Vanillin in ex vivo and in vitro assay systems While these studies implicate senescent cells in driving disc pathology, it remains to be established if senolytic drugs can slow, cure, or even prevent disc degeneration during physiological aging in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
