Abstract Body: Introduction: Ischemic stroke is a devastating brain injury and a leading cause of mortality and morbidity worldwide. Age is the most influential co-morbidity, modulating stroke severity, occurrence, and cognitive impact. We have previously found that stroke causes a marked increase in cellular senescence and senescence-associated secretory phenotype (SASP). In the aged brain, cells develop into SASP which induces neuroinflammation and further transform the healthy cell to senescent cells (SC) via paracrine signaling. Although there is a baseline amount of SCs in the aged brain, accumulating evidence suggests that pathological insults, such as stroke, traumatic brain injury, infection, cause a stress-induced premature senescent (SIPS) event. This event forces the healthy cells into SC’s, propagating brain injury and weakening neuroprotective mechanisms via release of SASP markers. However, the role of SC’s in the penumbra development has not yet evaluated.
Hypothesis: Senescent cells and SASP originating from the ischemic core induce a senescent penumbra, which contributes to ischemic damage in an age-dependent manner.
Methods: Middle cerebral artery occlusion was induced in young (7 weeks) and aged (16 months) C57 male mice using the photothrombotic model. Sham and stroked brains were perfused and then hemispheres were harvested and fresh frozen separately for protein and mRNA analysis of markers of SASP, senescence, and inflammation by western blot, qPCR, and immunofluorescence.
Results: Induction of stroke causes increased expression of key markers of cellular senescence such as IL-1α, IL-6, p21, p16 and CXCR2 in the ischemic penumbra. This expression is more pronounced in the young- stroked mice than the aged-stroked mice compared to age-matched sham mice with comparable infarct volume. Stroke did not cause further increase in SASP significantly in aged animals.
Conclusion: Senescence and SASP in the peri-infarct area are greatly associated with stroke in an age-dependent manner. Therefore, senescent cells in the penumbra are a key contributor to post-stroke brain injury. Modulation of Senescence and SASP would be a therapeutic avenue for the management of severity of post-stroke brain.