SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine.
4 affiliations
- 1Department of Orthopedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
- 2Labcorp, Morrisville, North Carolina, USA.
- 3Division of Biostatistics and Bioinformatics, Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
- 4Center for Translational Bioinformatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract
Aging is a critical risk factor for intervertebral disc degeneration, a major contributor to chronic low back pain. Loss-of-function studies showed that SIRT6, a nuclear NAD⁺-dependent deacetylase, maintains disc health. We therefore investigated whether long-term SIRT6 activation via systemic delivery of the small-molecular agonist MDL-800 improves disc health in 24-month-old mice. Studies revealed healthy disc morphology, enhanced cell viability, and lower degeneration scores following MDL-800 treatment. SIRT6 activation decreased H3K9ac levels, improved extracellular matrix quality, and reduced senescence, as evidenced by lower levels of p21, IL-6, TGF-β, and CCL2. Tissue RNA-Seq, measurements of histone 3 modification, and multi-omics ATAC-seq/RNA-seq revealed altered epigenetic (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscapes. MDL-800 increased autophagy without affecting disc cellular bioenergetics. Plasma metabolomics, scRNA-sequencing of lymphoid tissues (bone marrow and spleen), and cytokine profiling showed good systemic tolerance of the treatment. While we noted a small decrease in vertebral structural parameters and mild hyperalgesia in treated cohorts, there were no vertebral fractures, and the broader motor function and behavior remained unaffected, raising no safety concerns. Our studies underscore the feasibility of SIRT6 activation as a pharmacological strategy to maintain the health of the aging spine.
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BibTeX
@article{ramteke2026sirt6,
title = {{SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine.}},
author = {Pranay Ramteke and Bahiyah Watson and Sanjana Jagannath and Sarah E Bell and Mallory Toci and Olivia Ottone and Qinglin Wu and Oliver Abinader and Ramkrishna Mitra and John A Collins and Ruteja A Barve and Makarand V Risbud},
journal = {Aging cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70709},
url = {https://europepmc.org/article/MED/42895774},
note = {CC BY},
}
RIS
TY - JOUR
TI - SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine.
AU - Pranay Ramteke
AU - Bahiyah Watson
AU - Sanjana Jagannath
AU - Sarah E Bell
AU - Mallory Toci
AU - Olivia Ottone
AU - Qinglin Wu
AU - Oliver Abinader
AU - Ramkrishna Mitra
AU - John A Collins
AU - Ruteja A Barve
AU - Makarand V Risbud
PY - 2026
DA - 2026/10/01
JO - Aging cell
DO - 10.1111/acel.70709
UR - https://europepmc.org/article/MED/42895774
AB - Aging is a critical risk factor for intervertebral disc degeneration, a major contributor to chronic low back pain. Loss-of-function studies showed that SIRT6, a nuclear NAD⁺-dependent deacetylase, maintains disc health. We therefore investigated whether long-term SIRT6 activation via systemic delivery of the small-molecular agonist MDL-800 improves disc health in 24-month-old mice. Studies revealed healthy disc morphology, enhanced cell viability, and lower degeneration scores following MDL-800 treatment. SIRT6 activation decreased H3K9ac levels, improved extracellular matrix quality, and reduced senescence, as evidenced by lower levels of p21, IL-6, TGF-β, and CCL2. Tissue RNA-Seq, measurements of histone 3 modification, and multi-omics ATAC-seq/RNA-seq revealed altered epigenetic (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscapes. MDL-800 increased autophagy without affecting disc cellular bioenergetics. Plasma metabolomics, scRNA-sequencing of lymphoid tissues (bone marrow and spleen), and cytokine profiling showed good systemic tolerance of the treatment. While we noted a small decrease in vertebral structural parameters and mild hyperalgesia in treated cohorts, there were no vertebral fractures, and the broader motor function and behavior remained unaffected, raising no safety concerns. Our studies underscore the feasibility of SIRT6 activation as a pharmacological strategy to maintain the health of the aging spine.
SN - 1474-9718
SN - 1474-9726
ER -