SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine

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.