...Here, we demonstrate that systemic transplantation of adult multipotent muscle-derived stem/progenitor cells (MDSPCs)-isolated from young mice-rejuvenates the knee articular cartilage (AC) of naturally aged mice. This intervention reduced expression of pro-inflammatory cytokines (Tnf and Il1a) and catabolic matrix-degrading proteinases (Mmp3 and Mmp13) in aged cartilage. Treatment with young MDSPCs also increased expression of pro-regenerative (Col2a1 and Acan) and prolongevity genes (Pot1b), including those associated with chondrocyte proliferation and differentiation, cartilage growth, and telomere protection. Indeed, the AC of MDSPC-treated mice exhibited reduced age-related histological pathologies. Importantly, the reduced mobility and arthritis-related gait dysfunctions of aged mice were also ameliorated by this treatment. Together, our findings demonstrate the rejuvenating effects of systemic transplantation of young MDSPCs on aging AC-at the molecular, tissue, and functional levels. This suggests that MDSPCs, or their secreted factors, may represent a novel therapy that can increase mobility and function in aged or OA patients.