image: a Schematic showing Sirt6 floxed allele which following Cre-mediate recombination generates a functionally null mutant allele. b Experimental design showing the timeline of tamoxifen injection and analysis of control (Sirt6fl/fl) and sirt6 loss (Sirt6AcanCreERT2/Sirt6cKO) mouse cohorts. c Immunofluorescence staining for H3K9ac shows a robust increase in NP, AF and EP compartment of the lumbar disc confirming the deletion of SIRT6. d Safranin-O/Fast Green staining of Sirt6fl/fl and Sirt6cKO lumbar discs at 12 and 24 months. Scale bar 1A: row 1 = 200 μm; row 2 = 50 μm. e, f Distribution of and (e', f' average modified thompson's grades of lumbar discs of Sirt6fl/fl and Sirt6cKO mice analyzed at 12 and 24 months. 12 months: n = 4–6 mice/group, 3–4 discs/animal. 24 months: n = 3–6 animals/mice, 3–4 discs/animal. g-g"' Level by level average modified Thompson grading scores for NP and AF compartments of lumbar discs analyzed from 12 and 24 months Sirt6fl/fl and Sirt6cKO mice. h μCT analysis showing (i-i") Disc height (DH), Vertebral height (VB) and Disc height index (DHI) measured at 12 months and 24 months. j TUNEL staining images and (k-k") TUNEL quantitation. Statistical difference between grade distributions (e, f) was tested using chi-square test, all other quantitative data was compared using unpaired t-test, *P < 0.05.
Credit: The authors (Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria A. Tran, Shira Johnston, Maria Tsingas, Ruteja A. Barve, Ramkrishna Mitra, Richard F. Loeser, John A. Collins & Makarand V. Risbud)
As populations worldwide continue to age, chronic back pain caused by intervertebral disc degeneration is emerging as a widespread and costly health burden. Now, researchers have uncovered a key genetic regulator that may hold the secret to slowing this degenerative process. A new study reveals that Sirtuin 6 (SIRT6), an epigenetic enzyme, plays a vital role in preserving spinal disc integrity by suppressing cellular aging. Using a genetically modified mouse model, scientists found that removing SIRT6 from disc cells led to early-onset degeneration—marked by DNA damage, disorganized collagen fibers, and heightened inflammatory activity. These findings illuminate a molecular pathway behind age-related spinal deterioration and suggest that enhancing SIRT6 activity could offer a new path for non-invasive treatments.
Low back pain is the most prevalent musculoskeletal condition worldwide and is closely tied to the progressive degeneration of intervertebral discs. Aging remains the strongest risk factor for this condition, yet the molecular mechanisms that drive age-related disc breakdown have remained elusive. Among the Sirtuin family of proteins, Sirtuin 6 (SIRT6) has gained attention for its roles in DNA repair, chromatin remodeling, and aging regulation across various tissues. While its protective effects in bone and cartilage have been noted, its function in the spinal disc—an avascular and structurally unique tissue—has not been fully understood. Given the vulnerability of disc tissue to aging, exploring SIRT6's role in disc maintenance is both timely and essential.
A collaborative research team led by scientists at Thomas Jefferson University has now identified SIRT6 as a critical safeguard of spinal disc health. In findings (DOI: 10.1038/s41413-025-00422-3) published March 4, 2025, in Bone Research, the team used a mouse model engineered to lack SIRT6 specifically in disc tissues. These mice exhibited rapid and severe disc degeneration, even at a relatively young age, closely mirroring the pathology seen in aging human spines. By integrating tissue analysis with transcriptomic and epigenetic data, the researchers showed that SIRT6 loss disrupted cellular balance, triggering inflammation, chromatin changes, DNA damage, and signs of premature cellular aging.
Mice lacking SIRT6 in their disc cells (Sirt6cKO) began to show clear signs of degeneration by 12 months of age, with symptoms worsening significantly by 24 months. Structural breakdown was observed in both the nucleus pulposus and annulus fibrosus. At the molecular level, SIRT6 deletion caused excessive acetylation of histone H3K9, impaired autophagy, and accumulation of DNA damage. These effects were accompanied by a rise in senescence-associated secretory factors such as IL-6, TGF-β, and p21. Further in vitro studies in rat disc cells confirmed these findings, showing parallel shifts in gene expression and histone modifications upon SIRT6 knockdown. Cross-comparison of the datasets revealed key dysregulated pathways related to extracellular matrix remodeling, NF-κB signaling, and tissue fibrosis. Notably, the discs showed reduced collagen I, accumulation of denatured collagen, and elevated expression of hypertrophic markers—hallmarks of disc matrix breakdown and cellular dysfunction.
"SIRT6 acts as a powerful epigenetic regulator in spinal discs, and its absence leads to a cascade of degeneration-related events," explained Dr. Makarand Risbud, the study's senior author. "Our work demonstrates that without SIRT6, disc cells enter a senescent state much earlier, triggering structural collapse and inflammation. These findings not only expand our understanding of disc aging but also open the door to developing SIRT6-based therapies that could delay or prevent degeneration."
The study presents compelling evidence that SIRT6 is indispensable for maintaining disc integrity as the body ages. By mapping the genetic and epigenetic disruptions triggered by its loss, the research highlights new therapeutic targets for age-associated spinal degeneration. Activating SIRT6 pharmacologically may offer a novel, non-surgical option for preserving disc function and preventing chronic back pain. As the demand for healthy aging solutions grows, strategies aimed at restoring SIRT6 activity could help extend spine health and improve quality of life for millions.
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References
DOI
Original Source URL
https://doi.org/10.1038/s41413-025-00422-3
Funding information
This study was supported by the Michael Michelson Gift Fund and NIA grants R01AG073349 (M.V.R.), R01AG044034 (R.F.L.), and R01AG078609 (J.C.). Some aspects of this research were conducted while J.C. was an Irene Diamond Fund/AFAR Postdoctoral Transition Awardee in Aging.
About Bone Research
Bone Research was founded in 2013. As a new English-language periodical, Bone Research focuses on basic and clinical aspects of bone biology, pathophysiology and regeneration, and supports the foremost discoveries resulting from basic investigations and clinical research related to bone. The aim of the Journal is to foster the worldwide dissemination of research in bone-related physiology, pathology, diseases and treatment.
Journal
Bone Research
Subject of Research
Not applicable
Article Title
Sirt6 deficiency promotes senescence and age-associated intervertebral disc degeneration in mice
Article Publication Date
8-May-2025
COI Statement
The authors declare that they have no competing interests.