Fig. 4

Cellular senescence and other age-related mechanisms in IVD accelerate IVDD. With age, NPCs lead to ECM breakdown through decreased CTGF/CCN2 and increased SASP secretion. An increase in Piezo1 and a decrease in circERCC2 were also observed in senescent NPCs. Blockade of the Keap1/Nrf2/Wnt5a axis or activation of the cGAS/STING axis promoted the senescence of NPCs. Furthermore, ROS accumulation, p53/p21 activation, GLRX3 dysregulation, a lack of NLRX1, and TNF infiltration also contributed to the senescence of NPCs. Decreased SHH secretion in senescent NPCs leads to loss of polarity and the characteristic hierarchical structure of AFCs. ROS accumulation and deletion of Keap1/Nrf2/Wnt5a, CD133⁺, Notch1, Jagged1, C-KIT, and CD166 trigger senescence in AFCs. Decreased proteoglycan secretion and increased X-type collagen secretion in CEPCs led to calcification of the ECM. Calcified CEPCs limit nutrient and oxygen uptake, thereby disrupting IVD homeostasis. Senescent OCs induce pain via Netrin-1 by inducing sensory nerves into the aging endplate. Abnormal stress activates Hippo signaling to initiate cartilage endplate remodeling. Senescent macrophages induce endplate sclerosis by secreting IL-10. These factors ultimately contribute to the cellular changes associated with aging and the development of IVDD. The red frames represent upregulated genes, and the blue frames represent down-regulated genes