Senescent cells accumulate with age, generating disruptive inflammatory signaling that is disruptive to tissue structure and function. Numerous research groups and companies are developing therapies capable of either selectively destroying senescent cells or dampening their signaling. Animal studies and initial human trials suggest that the earliest senolytic treatments used to clear senescent cells, derived from cancer therapies, are safe and effective enough for widespread use. The drugs and compounds used cost relatively little, which is a meaningful argument for greater exploration of their utility. Unfortunately they are not a point of focus outside academia and a small number of anti-aging physicians. Few studies have directly compared first generation senolytic treatments, so the data noted here is interesting for supporting the dasatinib and quercetin combination over navitoclax.
Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ).
While Nav. treatment did not improve severe degeneration in SM/J mice or senescence status, DQ-treated mice showed lower grades of degeneration and a decreased abundance of senescence markers, including p19ARF, p21, and the senescence-associated secretory phenotype (SASP). DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis revealed tissue-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across different tissue types. A comparison of SM/J data with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6 N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc.
Notably, the in vitro inhibition studies of the JUN pathway in human degenerated NP cells mimicked the benefits of DQ, namely, a reduction in senescence and SASP. This study reinforces the efficacy of senolytic treatment in ameliorating local senescence and intervertebral disc fibrosis.
