Bone aging: a paradigm of multiscale degeneration and targeted rejuvenation

Bone aging is not merely a process of bone mass loss but rather a multi-level, networked degenerative phenomenon spanning molecular, cellular, tissue, and system levels. With the accelerating pace of global population aging, bone degenerative diseases have emerged as a major public health challenge. Consequently, there is an urgent need to elucidate the underlying mechanisms from an integrated perspective and to develop innovative intervention strategies. This review systematically synthesizes the comprehensive landscape of bone aging. At the macroscopic level, bone aging is characterized by declines in bone mass, microstructure, and biomechanical properties, ultimately leading to increased fragility. At the microscopic level, its pathogenesis involves dysfunction across multiple layers. Molecular mechanisms include genetic and epigenetic alterations, oxidative stress, the senescence-associated secretory phenotype, and dysregulation of key signaling pathways. Cellular level changes involve telomere attrition, mitochondrial and endoplasmic reticulum dysfunction, impaired proteostasis, altered nutrient sensing, and cellular senescence. At the microenvironmental and systemic levels, contributing factors include chronic inflammation, hormonal changes, and extracellular matrix remodeling. Correspondingly, intervention strategies include non-pharmacological approaches, such as dietary optimization, physical activity, and avoidance of alcohol and tobacco, as well as pharmacological therapies, including antiresorptive agents, anabolic bone-forming drugs, and senolytics. Emerging therapeutic avenues include regenerative medicine, gene therapy, and tissue engineering. Future research should focus on constructing a multi-omics-integrated bone aging atlas, developing bone organoids and computational models, establishing multimodal risk assessment systems, advancing precision therapies that target aging-related pathways, and promoting prevention-centered public health strategies. This review aims to provide a systematic framework for understanding the complex pathophysiology of bone aging and to provide key insights and directions for future interdisciplinary collaborations, translational research, and clinical interventions.