Background. Osteoarthritis (OA) is one of the most prevalent joint diseases of advanced age and is a leading cause of disability worldwide. Ageing is a major risk factor for the articular cartilage (AC) degeneration that leads to OA, and the age-related decline in regenerative capacity accelerates OA progression. Here we demonstrate that systemic transplantation of a unique population of adult multipotent muscle-derived stem/progenitor cells (MDSPCs), isolated from young wild-type mice, into Zmpste24 - / - mice (a model of Hutchinson-Gilford progeria syndrome, a condition marked by accelerated ageing), prevents ageing-related homeostatic decline of AC. Results. MDSPC treatment inhibited expression of cartilage-degrading factors such as pro-inflammatory cytokines and extracellular matrix-proteinases, whereas pro-regenerative markers associated with cartilage mechanical support and tensile strength, cartilage resilience, chondrocyte proliferation and differentiation, and cartilage growth, were increased. Notably, MDSPC transplantation also increased the expression level of genes known for their key roles in immunomodulation, autophagy, stress resistance, pro-longevity, and telomere protection. Our findings also indicate that MDSPC transplantation increased proteoglycan content by regulating chondrocyte proliferation. Conclusions. Together, these findings demonstrate the ability of systemically transplanted young MDSPCs to preserve a healthy homeostasis and promote tissue regeneration at the molecular and tissue level in progeroid AC. These results highlight the therapeutic potential of systemically delivered multipotent adult stem cells to prevent age-associated AC degeneration.