SIRT6 identified as a critical health protection of the spinal disc

Lumbar pain is the most frequent musculoskeletal condition throughout the world and is closely linked to the progressive degeneration of intervertebral discs. Aging remains the strongest risk factor for this condition, however, the molecular mechanisms that drive the decomposition of the age related to age have remained difficult to achieve. Among the Sirtuin protein family, Sirtuin 6 (SIRT6) has drawn attention for its roles in DNA repair, chromatin remodeling and aging regulation in several tissues. Although its protective effects on bone and cartilage have been observed, its function on the spinal disc, an avascular and structurally unique tissue, it has not been completely understood. Given the vulnerability of the disc of the aging, to explore the role of SIRT6 in the maintenance of the disk is timely and essential.

A collaborative research team led by scientists from Thomas Jefferson University has now identified Sirt6 as a critical health protection of the spinal disc. In findings (DOI: 10.1038/S41413-025-00422-3) published on March 4, 2025, in Bone Research, the team used a mouse model designed to lack SIRT6 specifically in disc tissues. These mice exhibited a fast and severe disk degeneration, even at a relatively young age, closely reflecting the pathology observed in the aging of human spines. When integrating tissue analysis with transcriptomic and epigenetic data, researchers showed that SIRT6 loss interrupted cell balance, triggering inflammation, chromatin changes, DNA damage and premature cell aging signs.

The mice that lacked Sirt6 in their disk cells (Sirt6cko) began to show clear signs of degeneration at 12 months of age, with symptoms that worsen significantly in 24 months. The structural decomposition was observed both in the pulposo nucleus and the Annulus fibrosus. At the molecular level, the SIRT6 deletion caused the excessive acetylation of the H3K9 histone, the deteriorated autophagy and the accumulation of the DNA damage. These effects were accompanied by an increase in the secretory factors associated with senescence such as IL-6, TGF-β and P21. More in vitro studies in rat cells confirmed these findings, showing parallel changes in gene expression and histone modifications after the elimination of Sirt6. The cross comparison of the data sets revealed deregulated key paths related to the remodeling of the extracellular matrix, the signage of NF-κB and tissue fibrosis. In particular, the discs showed a reduced and reduced collagen, the accumulation of denatured collagen and a high expression of hypertrophic markers, decomposition marks of the disk matrix and cell dysfunction.

Sirt6 acts as a powerful epigenetic regulator on spinal discs, and its absence leads to a waterfall of events related to degeneration. Our work shows that without Sirt6, disc cells enter a senescent state much earlier, which causes a structural collapse and inflammation. These findings not only expand our understanding of the aging of the disc, but also open the door to the development of SIRT6 -based therapies that could delay or prevent degeneration. “

Dr. Makarand Risbud, main author of the study

The study presents convincing evidence that Sirt6 is indispensable to maintain the integrity of the disk as the body ages. When mapping genetic and epigenetic interruptions triggered by its loss, research highlights the new therapeutic objectives for age associated with age. The activation of SIRT6 can offer a novel and non -surgical option to preserve the function of the disc and prevent chronic back pain. As the demand for healthy aging solutions grows, the strategies aimed at restoring SIRT6 could help extend the health of the column and improve the quality of life for millions.