Figure 1. Summary of human skeleteal stem cell based age-related alterations leading to bone loss and impaired regenerative capacity. A young functional hSSC is clonally diverse and abundantly gives rise to cell of the skeletal lineages as well as bone marrow supporting stroma. During aging lineage output is skewed which could underlie cellular senescence due to chronological aging or changes forced by an altered microenvironment. Future studies have to explore if aging of hSSCs, similar, to hematopoiesis, leads to clonal expansion of clones with specific characteristics, e.g. preferred fibroblast lineage generation. As a consequence of shifted differentiation to specific stromal lineages not only bone formation is impaired but also bone resorption is increased. Some of these changes might be the consequence of the loss of SIRT1 expression and reactivation could be a potent therapeutic means to restore youthful hSSC function and thereby reverse age-related bone loss.