Senescence Gene Expression Profiles and 90-Day Outcome in Stroke Patients

Understanding the biological determinants of stroke outcome is essential to improve treatment strategies. Cellular senescence may contribute to vascular dysfunction with age and has been linked to poor outcomes across a range of diseases. However, the role of senescence on stroke outcome in patients is not well defined. We sought to investigate the relationship between enriched senescence-associated gene signature expression and functional outcome after stroke.

Acute ischemic stroke patients and control participants were recruited from University of Alberta Hospital. Control (non-stroke) participants had stroke risk factors and were of similar age and sex to the stroke patients. Whole-blood gene expression was measured by microarray. Senescence signature expression was evaluated to quantify senescence enrichment by gene set enrichment analysis. Outcome was determined using the modified Rankin Scale (mRS) at 90 days after stroke onset. The relationship between senescence, age, risk factors, and stroke outcome was analyzed through ordinal logistic regression.

We included 129 acute ischemic stroke patients ≥60 years old, with a mean age of 77.3 ± 9.9 years and 41.9% female, and 41 control participants, with a mean age of 76.5 ± 7.9 years and 56.1% female. Patients with poor outcome (mRS > 2) had enriched senescence gene expression compared with those with good outcome (mRS ≤ 2); control participants also showed significant differences in senescence enrichment compared with the stroke outcome groups. High senescence was associated with a shift toward worse mRS scores (OR: 2.32; 95% CI 1.05-5.97) adjusted for age, sex, stroke severity, and type 2 diabetes mellitus. Senescence increased with age with variability across different ages. Among the senescence-associated genes, most differentially expressed between outcome groups were the epidermal growth factor receptor (EGFR) ligands amphiregulin and epiregulin, and the C-C motif chemokine ligand 16.

Increased senescence was associated with worse stroke outcome. These findings suggest that blood cell senescence may contribute to vascular aging and worse stroke outcome, likely by altering epidermal growth factor receptor signaling, increasing inflammation and blood-brain barrier disruption. This study provides translational evidence that measuring senescence may reflect a biological aging process that influences functional outcome after stroke.