Aging is associated with functional decline and reduced regenerative capacity in the brain, is also the strongest risk factor for ischemic stroke, which remains a leading cause of mortality and long-term disability worldwide, and is associated with impaired functional recovery. Here, we investigated whether short-term partial cellular reprogramming through cyclic expression of Yamanaka factors (OSKM) in a Tet-ON mouse model under Rosa-26 promoter has any impact on ischemic damage in aged mice. To assess ischemic resilience, mice underwent permanent middle cerebral artery occlusion (pMCAo). Forty-eight hours after ischemia, OSKM-induced mice displayed significantly smaller damaged area compared with wild-type controls, accompanied by improved neurological scores and enhanced performance in the tightrope test, suggesting preserved sensorimotor abilities. Notably, myelin integrity was preserved in OSKM-treated mice, as shown by Black-Gold staining and stable MAG and MBP expression, whereas wild-type mice exhibited pronounced demyelination. Given the role of oligodendrocytes in myelin maintenance, we quantified the abundance of their different populations. OSKM induction significantly increased total oligodendrocytes (Olig2+) and oligodendrocyte precursor cells (PDGFRα+) following ischemia, suggesting an enhanced reparative response. Moreover, partial reprogramming preserved neuronal density in the ischemic cortex and prevented the marked astrocytic activation observed in wild-type mice, while microglial responses remained comparable across genotypes. These findings demonstrate that cyclic partial reprogramming in aged mice reduces ischemic damage, highlighting OSKM induction as a promising strategy for enhancing brain resilience during cerebrovascular accidents.
