In adults, mesenchymal stromal cells contain tissue-specific multipotent stem cells, MSC, which can be found throughout the body. With advancing age, tight controls of regulatory networks, which guide MSC biology, gradually deteriorate. Aberrations within the MSC microenvironment such as chronic inflammation eventually lead to adverse manifestations, such as the accumulation of fat deposits in bone and muscles, impaired healing and fibrosis after severe injury, or altered hematopoiesis and autoimmunity. MSC can also specifically interact with a large variety of immune cells, and in doing so, they secrete cytoprotective and immunoregulatory molecules, which together with intercellular contacts mediate immune modulatory processes. This review comprehends the current knowledge regarding molecular mechanisms and cellular interactions that occur in stem cell niches, which are jointly shared between MSC and hematopoietic stem and progenitor cells, as well as those intracellular interdependences taking place between mesenchymal and a wide variety of hematopoietic progeny in particular T lymphocytes, which eventually perturb tissue homeostasis and immunology at advanced age.