<p>Sample Characteristics and stratified by stroke.</p>

Eight DNA methylation-based biological aging clocks were assessed. GrimAge was constructed as a composite marker calculated from epigenetic surrogate markers for select plasma proteins (adrenomedullin, beta-2-microglobulim, cystatin C, GDF-15, leptin, plasminogen activation inhibitor 1, tissue inhibitor metalloproteinases 1) and smoking-pack years. The study population included 3,467 individuals, with median age = 71 years, 59% were female and 295 individuals had stroke, Individuals with stroke had accelerated biological age compared to those without stroke.

Biological age was a prominent mediator in post-stroke short-term cognition (Pure Natural Indirect Effect (PNIE) = −0.47; P < 0.001), with a similar pattern in intermediate-term cognition (PNIE = −0.48, P < 0.001). TGF-Beta stood out among immunoinflammatory biomarkers, with strong interactive effects in post-stroke cognition, particularly in the short-term (Reference interaction effect (INTREF) = −2.09; P < 0.001). Some mediation effects through White blood cells in relation to short-term cognition, were observed (PNIE = −0.02; P = 0.03).

Joint mediation effects, through biological aging and immunoinflammatory biomarkers combined, were observed. Conclusions. DNA methylation-based biological aging and cytokines, TGF-Beta in particular, showed characteristic mediative and interactive roles, respectively, in post-stroke cognition.

DNA methylation-based biological aging combined with immunoinflammatory checkpoints open novel avenues for therapeutic and prognostic regulation of post-stroke cognition and cognitive resilience.</p></div>