From local to systemic: Spinal aging in the multi-organ aging network

Spinal aging is a progressive degenerative process involving structural and functional decline of the spine as a whole and of its individual components, ultimately contributing to the development of degenerative spinal diseases (DSDs). Previous studies have largely focused on local spinal tissues or the intervertebral disc (IVD). However, recent advances in geroscience indicate that spinal degeneration is not an isolated local event, but is influenced by systemic aging through a multi-organ aging network. Accordingly, this review proposes a "from local to systemic" framework to better understand the mechanisms underlying spinal aging. At the local level, spinal aging follows heterogeneous trajectories, with intervertebral disc degeneration (IVDD) often serving as a central process. Different DSDs share common pathological mechanisms, and their anatomical proximity allows them to interact biomechanically. Therefore, the spine should be regarded as an integrated organ system within systemic aging. Based on this concept, we propose that vertebral osteoporosis and paraspinal muscle degeneration should also be incorporated into the framework of spinal aging and DSDs. At the systemic level, immunosenescence, skeletal muscle aging, neural and vascular aging, digestive system aging, endocrine system aging, and nutrient-sensing dysregulation may collectively affect the spine through circulating inflammatory factors, senescence-associated secretory phenotypes, metabolic mediators, endocrine signals, and mechanical loading, thereby influencing the susceptibility, progression, clinical phenotypes, and treatment responses of DSDs. We further discuss clinical translation in spinal aging, including anatomical barriers to drug delivery and emerging strategies to overcome them, and summarize therapeutic approaches based on multi-organ aging. Ultimately, this review emphasizes that future DSDs treatment should achieve more precise stratification, move beyond lesion-centered local interventions, and incorporate systemic anti-aging strategies to optimize long-term clinical outcomes in patients with DSDs.