AbstractPartial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c‐Myc induces rejuvenation and reduces aged‐cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson‐Gilford progeria syndrome (HGPS). We observed that the dCas9‐Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator‐mediated Oct4 induction. Importantly, CRISPR/dCas9‐activated Oct4 expression rescued the HGPS‐associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9‐mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.