Senolytics as a Treatment for Intervertebral Disc Degeneration

Degenerative disc disease is commonplace, and in recent years research has implicated the age-related accumulation of senescent cells in the onset and progression of this condition. Senolytic drugs to clear senescent cells may thus be a useful treatment. Existing senolytics, such as the dasatinib and quercetin combination, could be applied to many age-related conditions, since senescent cells and their inflammatory secretions produce broad negative effects on cell and tissue function. Unfortunately there is little funding and financial incentive for academic organizations to run clinical trials for even a significant fraction of these conditions.

Intervertebral disc degeneration (IVDD) refers to an age-related change that mainly occurs in the lumbar intervertebral disc and often precedes other age-related changes. During the process of IVDD, annulus fibrosis (AF), one of the important compositions of intervertebral disc, loses its original layer and toughness, and reticulated degeneration and hyalinization appear, while the percentage of water decreases in another component called nucleus pulposus (NP). As a result, the intervertebral disc loses its normal elasticity and tension.

Aging is the primary risk factor for the development of IVDD, which causes the accumulation of senescent cells in the intervertebral disc. Researchers have found that senescent NP cells play an important role in the initiation of IVDD. The number of senescent NP cells increased significantly during IVDD, suggesting the deleterious effect of senescent NP cells on the pathogenesis of IVDD. Recent studies have shown that senescent cells could secrete metabolic factors such as pro-inflammatory cytokines, matrix-degrading proteases, growth factors://">growth factors, and chemokines, which caused changes of the extracellular matrix (ECM). In addition, senescent cells can affect adjacent cells through paracrine signaling, thereby inducing the catabolism and inflammation in the microenvironment of intervertebral disc. The metabolic factors secreted by senescent cells are collectively named senescence-associated secretory phenotype (SASP).

In recent years, investigations on new drugs that target the process of senescence have become a new therapeutic strategy for the early prevention and latter treatment for degenerative diseases. Evidence suggest that whether through genetically modified strategy or chemotherapy, the elimination of p16INK4a senescent cells has been shown to significantly extend the healthspan in murine models. So, optimizing treatments to reduce senescence or eliminate senescent cells may exert positive effects on human health. Senolytic represents a wide range of drugs or small molecules that can selectively eliminate senescent cells. The application of senolytic drugs is a potential strategy for degenerative disease treatment, including IVDD.



Another issue is that senolytics would probably be more effective at preventing IVDD than in actively repairing it after the damage is done. This means you would probably need an even larger trial to see the effects, since not everyone at risk will develop IVDD.

On the other hand, you could also piggyback on any senolytic trial which does run by surveying the participants to see how many people taking senolytics developed IVDD (or various other issues) later, compared to the general population (with a retrospective survey to adjust in case the baseline was higher or lower than the population by some chance; or even better if it has a control group). Are there any well-powered senolytic trials running these days?

Posted by: Liberty at April 1st, 2022 9:53 AM

If only could raise enough funds to run a small trial of dasatinib + quercetin vs lower back disk degeneration.

Posted by: jimofoz at April 1st, 2022 1:44 PM

Why not use fisetin ?

Posted by: JLH at April 4th, 2022 8:43 AM

Easier and cheaper than D and Q.

Posted by: JLH at April 4th, 2022 8:44 AM

"Why not use fisetin ?" 'cause it doesn't work or work too little to make any difference on this kind of cells / illness? Curcumin is a weaker senolytic than fisetin overally, but is better on intervertebral disc. There is still too much selectivity of a given senolytic on cell types.

Posted by: SilverSeeker at April 4th, 2022 12:37 PM
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