SAMP6 mice exhibit features of skeletal aging including reduced bone mineral density (BMD), diminished rate of bone formation, fewer mesenchymal stem cell (MSC) progenitors of osteoblasts, decreased osteoblasts and increased marrow adipocytes. A decrease in the self-renewal capacity of MSCs may account for the reduced osteoblast number and bone formation. Increased activation, or overexpression, of the transcription factor PPARγ2 in SAMP6 mice may also contribute as features of the SAMP6 skeletal phenotype were reproduced by feeding the PPARγ2 ligand rosiglitazone to normal mice. Genetic mapping studies utilizing F2 progeny of SAMP6 mice mated with either SAMR1 or the related AKR/J strain identified quantitative trait loci (QTLs) for vertebral BMD on chromosomes 2, 7, 11, 13, 16, 18, and X. Transfer of the AKR allele of the chromosome 2 QTL into SAMP6 mice by backcrossing caused a 5.0-5.4% increase in BMD, accounting for ~50% of the BMD difference between SAMP6 and AKR/J. Studies in Scottish postmenopausal women revealed an association of the X chromosome locus with BMD, thus demonstrating the applicability of QTL mapping information derived from mice to humans. Future genetic and functional studies of SAMP6 mice should therefore provide clues as to why the production of osteoblasts is reduced during aging in mice and humans.