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This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD. We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the \u201cepigenetic aging clock\u201d and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-dCas9 editing, and cellular reprogramming approaches ranging from iPSC differentiation to direct lineage conversion. We propose a synergistic \u201cclear, prime, then seed\u201d roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.<\/jats:p>","DOI":"10.3389\/fragi.2026.1842955","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:51:14Z","timestamp":1781671874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Resetting the epigenetic clock: cellular senescence and regenerative strategies in intervertebral disc degeneration"],"prefix":"10.3389","volume":"7","author":[{"given":"Minfan","family":"Li","sequence":"first","affiliation":[{"name":"Spinal Surgery Department, Mianyang Orthopaedic Hospital","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Deng","sequence":"additional","affiliation":[{"name":"Spinal Surgery Department, Mianyang Orthopaedic Hospital","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongda","family":"Xu","sequence":"additional","affiliation":[{"name":"Spinal Surgery Department, Mianyang Orthopaedic Hospital","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingzhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The Affiliated Hospital of Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Spinal Surgery Department, Mianyang Orthopaedic Hospital","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3390\/cells14030149","article-title":"Mesenchymal stem\/stromal cells microencapsulation for cell therapy","volume":"14","author":"Abbas","year":"2025","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nat. 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