Mechanical effects in aging of the musculoskeletal system: Molecular signaling and spatial scale alterations

The musculoskeletal system, the primary load-bearing structure of the human body, plays a crucial role in mechanotransduction, a process comprising mechanosensation, mechanotransduction, and mechanical effect. Aging leads to loss of ability of mechanosensitive cells to sense mechanical stimuli, disruption of transduction pathways, SASP and adiposity accumulation. At the mesoscopic level, bone, cartilage, and muscle differentiation decline, while adipogenesis increases, leading to extracellular matrix and structural aging, ultimately manifesting as macroscopic musculoskeletal degeneration. This review explores intercellular crosstalk and mechanotransduction alterations in aging from a mechanobiological perspective, providing insights into potential therapeutic targets for bone aging and osteoporosis. It also introduces the mesoscopic scale definition and trans mesoscopic transplantation therapy as novel strategies for fracture treatment, postoperative rehabilitation, and bone regeneration, offering innovative directions for future musculoskeletal research. The translational potential of this article: This article systematically reviews the effects of aging on the musculoskeletal system from a mechanobiological viewpoint, covering from microscopic molecular signaling to macroscopic spatial structural alterations, and proposes new strategies to complement the principles of AO therapy, optimization of braking, new insights into tumor metastasis and weight-bearing, and a new strategy for trans mesoscopic transplantation therapy. These insights will contribute to optimizing the management of geriatric fragility fractures in the elderly, exploring innovative therapies for the treatment of diseases of the aging musculoskeletal system, and facilitating the development of integrative therapies and precision medicine in the field of orthopaedics.