Intervertebral disc degeneration is a complex dysfunction in the tissue maintenance and tissue properties of the discs between vertebrae. The discs allow flexibility of the spine, cushion impacts, and hold the spine together. Weakening of disc structures leads to tears and other failures that produce a sizable negative impact on the ability of an individual to function. A large subset of the population shows measurable degeneration of intervertebral discs even before reaching age 40, and after that point it becomes a majority. This is a universal aspect of aging, and the question is only how long it will take before something important breaks under stress.
Interestingly, intervertebral disc degeneration is strongly connected to cellular senescence. There are clear lines to be drawn between the burden of senescent cells and the mechanisms leading to loss of disc structural integrity. Senolytic therapies to selectively clear senescent cells have done well in animal models of degenerative disc disorders. Similarly, mitochondrial dysfunction is also strongly linked to intervertebral disc degeneration. Both loss of mitochondrial function and burden of senescence are correlated – the former tends to increase the pace at which the latter grows. It is interesting to note today’s open access study, in which improved mitochondrial function also reduces cellular senescence in the course of restoring some lost function to an aged tissue.
Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration
Intervertebral disc degeneration is the principal pathological basis of low back pain. Currently, there are limited therapeutic strategies to regenerate intervertebral disc. In this study, we found the expression of SIRT3 is significantly negatively correlated with the degree of disc degeneration in humans. In mice, knockout of Sirt3 resulted in pronounced disc degeneration accompanied by increased expression of inflammatory mediators and senescence-associated factors.
Transcriptomic analyses in mice revealed that Sirt3 deficiency was closely associated with dysregulation of calcium signaling pathways and impaired adenosine triphosphate (ATP) synthesis. Bioinformatics analyses identified Ckm and Atp2a1 as hub genes linking Sirt3 deficiency to calcium homeostasis disruption and ATP metabolic dysfunction.
Importantly, the administration of Sirt3 activator 2-APQC in a D-galactose-induced aging mouse model significantly ameliorated intervertebral disc degeneration-associated pathological changes, evidenced by restored mitochondrial function, reduced inflammation and cellular senescence, and rescued expression of hub genes Ckm and Atp2a1.
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