From complexity to clarity: aging bone marrow niche in bone and blood regeneration and malignancy.

Abstract

The bone marrow niche (BMN) plays a central role in regulating hematopoietic stem-cell (HSC) maintenance, lineage commitment, and immune homeostasis, while also supporting osteogenesis and maintaining skeletal integrity. Once considered static, the BMN is now recognized as a dynamic and responsive microenvironment that integrates local signals and systemic cues to meet physiological demands and respond to stress. Aging causes profound and progressive changes to this niche, leading to functional decline across both hematopoietic and stromal compartments. Recent advances in high-resolution imaging, single-cell and spatial transcriptomics, and in vivo lineage tracing have revealed remarkable heterogeneity and plasticity within the vascular and mesenchymal elements of this niche. Yet, key questions remain unresolved, including the identity and hierarchy of mesenchymal and osteolineage cells, the specialization of subsets of endothelial cells, the integration of systemic regulation, and whether the aging bone marrow acts as a driver or a passenger in malignancy and chronic inflammation. This review revisits current models of the BMN, with a focus on the reciprocal interactions between osteogenic cells and specialized vasculature, and how their disruption during aging impairs hematopoietic output and skeletal remodeling. We also examine how systemic factors such as neural input, metabolic status, and inflammatory signaling influence the aging of the BMN. Finally, we highlight emerging translational platforms, including iPSC-derived bone marrow organoids, engineered niches/hydrogels, and vascularized organ-on-chip systems, that enable mechanistic testing of rejuvenation strategies. Together, these insights have the potential to pave the way toward targeted interventions that restore the function of the BMN and promote healthy aging of the bone and blood systems.