Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies

Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors—the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence—a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity, reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.