Aging is characterized by common environmental changes, such as hormonal, immunologic, and metabolic disorders. These pathologic factors impair the capability of mesenchymal stem cells (MSCs) to generate and maintain functionalized tissue components, contributing to age-related tissue degeneration (e.g., osteoporosis). However, in organismal aging, whether the microenvironmental signals induce common or differential MSC compromise and how they interact at the molecular level in mediating the functional decline of MSCs are not fully understood. In this review, we discuss the respective contribution of microenvironmental pathologic factors to age-related MSC dysfunction - particularly, the shifted differentiation from osteoblasts to adipocytes of bone marrow-derived MSCs. The authors summarize recent works regarding mechanisms underlying MSC-biased differentiation under altered microenvironments, which involve the activation of key signaling pathways, intracellular oxidative stress, and posttranscriptional regulations. In addition, we compare the differential influences of systemic and local microenvironments on MSC differentiation based on our findings. The authors also propose strategies to rescue differentiation disorders of MSCs in aging via modulating microenvironments, by using signaling modulators, anti-inflammatory agents, antioxidants, and metabolic regulators and by promoting mobilization of systemic MSCs to local injury sites. The authors hope that these insights contribute to MSC-based organismal aging research and treatments. © International & American Associations for Dental Research.