Aging of mesenchymal stem cells in bone aging: Mechanisms, impact, and therapeutic perspectives

Aging of the skeleton is a hallmark of organismal decline and underlies prevalent age-related disorders such as osteoporosis and osteoarthritis. Bone marrow-derived mesenchymal stem cells (BMSCs), the primary source of osteoblasts, undergo profound functional deterioration during senescence, leading to an imbalance between bone formation and resorption. This review systematically summarizes the key features of BMSC senescence, including impaired proliferation and differentiation, epigenetic dysregulation, and the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). We highlight recent advances in understanding how epigenetic mechanisms (DNA methylation, histone modifications, RNA methylation, and non-coding RNAs) orchestrate BMSC aging. In addition, we discuss the intricate crosstalk between senescent BMSCs and the bone microenvironment, emphasizing their contribution to age-related bone diseases. Finally, we propose future research directions, including the integration of multi‑omics, single-cell technologies, and targeted epigenetic interventions, as well as emerging therapeutic strategies such as senolytics, metabolic modulators, and extracellular vesicle-based approaches. A deeper understanding of BMSC aging will facilitate the development of novel treatments to preserve bone health and combat aging-related skeletal disorders.