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Loss\u2010of\u2010function studies showed that SIRT6, a nuclear NAD\n                    <jats:sup>+<\/jats:sup>\n                    \u2010dependent deacetylase, maintains disc health. We therefore investigated whether long\u2010term SIRT6 activation via systemic delivery of the small\u2010molecular agonist MDL\u2010800 improves disc health in 24\u2010month\u2010old mice. Studies revealed healthy disc morphology, enhanced cell viability, and lower degeneration scores following MDL\u2010800 treatment. SIRT6 activation decreased H3K9ac levels, improved extracellular matrix quality, and reduced senescence, as evidenced by lower levels of p21, IL\u20106, TGF\u2010\u03b2, and CCL2. Tissue RNA\u2010Seq, measurements of histone 3 modification, and multi\u2010omics ATAC\u2010seq\/RNA\u2010seq revealed altered epigenetic (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscapes. MDL\u2010800 increased autophagy without affecting disc cellular bioenergetics. Plasma metabolomics, scRNA\u2010sequencing 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.\n                  <\/jats:p>","DOI":"10.1111\/acel.70709","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:41:28Z","timestamp":1792424488000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SIRT6<\/scp>\n                    Activation Improves Intervertebral Disc Health in the Aging Spine"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4611-7680","authenticated-orcid":false,"given":"Pranay","family":"Ramteke","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7441-1076","authenticated-orcid":false,"given":"Bahiyah","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Jagannath","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7490-2528","authenticated-orcid":false,"given":"Mallory","family":"Toci","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9044-1832","authenticated-orcid":false,"given":"Olivia","family":"Ottone","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglin","family":"Wu","sequence":"additional","affiliation":[{"name":"Labcorp  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Abinader","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Bioinformatics, Department of Pharmacology Physiology, and Cancer Biology, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramkrishna","family":"Mitra","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Bioinformatics, Department of Pharmacology Physiology, and Cancer Biology, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5743-3304","authenticated-orcid":false,"given":"John A.","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1171-9761","authenticated-orcid":false,"given":"Ruteja A.","family":"Barve","sequence":"additional","affiliation":[{"name":"Center for Translational Bioinformatics, Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-0649","authenticated-orcid":false,"given":"Makarand V.","family":"Risbud","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201033"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","unstructured":"Barve R. 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