STUDY DESIGN: NF-κB activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes. OBJECTIVE: To study the mediatory role of NF-κB-signaling pathway in age-dependent intervertebral disc degeneration. SUMMARY OF BACKGROUND DATA: Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-κB is a family of transcription factors that play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-κB activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-κB inhibition on IDD, using a DNA repair-deficient mouse model of accelerated aging (Ercc1 mice) previously been reported to exhibit age-related IDD. METHODS: Systemic inhibition of NF-κB activation was achieved either genetically by deletion of 1 allele of the NF-κB subunit p65 (Ercc1p65 mice) or pharmacologically by chronic intraperitoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-κB, IκB Inducible Kinase (IKK), in Ercc1 mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice, and untreated controls were assessed. RESULTS.: Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-κB activity were observed in discs of progeroid Ercc1 mice and naturally aged wild-type mice compared with young wild-type mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1 mice increased disc proteoglycan synthesis and ameriolated loss of disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1p65 mice. CONCLUSION: These findings demonstrate that the IKK/NF-κB signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.