Mesenchymal stem cells (MSCs) are able to differentiate into distinct lineages such as adipo-, osteo-, and chondrocytes. MSCs were isolated from three mouse strains, which are short- (SAMP6, 9.7 months), medium- (SAMR1, 16.3 months), or long-lived (C57BL/6, 28 months). We investigated primary colony-forming units with regard to bone marrow stroma and found differences that correlate with mean life expectancies of the particular genetic backgrounds. However, MSC derived from the various mouse strains behaved equivalently in vitro with respect to growth rate. By genomic means, we analyzed the cellular milieu in vivo and found considerable differences among the various mouse strains. This implies that, although individual MSCs show an equivalent differentiation potential in vitro, the primary stem cells are greatly influenced by their molecular environment.