The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework

In the present study, we assessed the direct and indirect effects of stroke on short-term and intermediate-term cognition with respect to biological aging, inflammation and immunity. The study included individuals with stroke information at wave 12, who consented for blood draw in the Health and Retirement 2016 Venous blood study (wave 13) and had cognitive assessments through wave15. Four-way decomposition models were conducted. Inflammatory cytokines included: Interleukin-6 (IL-6), Interleukin-1RA (IL-1RA), Interleukin-10 (IL-10), tumor necrosis factor R1 (TNFR1) and transforming growth factor-beta (TGF-beta). Immunity biomarkers included: basophils, eosinophils, lymphocytes, monocytes, neutrophils and white blood cells. DNA methylation was used for biological age assessment. 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.