In this study, we presented several lines of evidence supporting a geroprotective role of YAP and FOXD1 in rejuvenating hMSCs: (1) YAP is required for preventing premature senescence of hMSCs; (2) YAP transcriptionally activates FOXD1 expression whereas YAP deficiency results in down-regulation of FOXD1, which contributes to the early-onset of cellular aging; and (3) lentiviral gene transfer of YAP or FOXD1 alleviates cellular senescence and osteoarthritis. The gene discussed is FOXD1; the disease is osteoarthritis.