{ "abstract": "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. Author summary: Cerebrovascular disorders including stroke affect cognitive health through complex biological pathways. In the present study, we investigated the interplay of biological aging based on DNA methylation, inflammation and immunity in cognition after stroke. We found that biological aging and immunoinflammatory pathways play distinct mediative and interactive roles in cognitive health after stroke and hence open novel avenues to monitor cognitive and brain health and improve cognitive resilience in aging.", "abstract_shown": true, "affiliations": [ "Department of Epidemiology, College of Public Health, Health Professions and College of Medicine, University of Florida, Gainesville, Florida, United States of America", "The Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, United States of America", "Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, United States of America", "Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 4, "authors": [ { "affs": [ 0 ], "name": "Reem Waziry" }, { "affs": [ 1 ], "name": "Caleb H. Miles" }, { "affs": [ 2 ], "name": "Olajide Williams" }, { "affs": [ 3 ], "name": "Henning Tiemeier" } ], "bibtex": "https://research.draconitic.com/paper/c0aybzc7hbad1.bib", "cited_by": 0, "doi": "10.1371/journal.page.0000033", "fulltext_url": null, "id": "c0aybzc7hbad1", "issns": [ "3070-801X" ], "landing_url": "https://doi.org/10.1371/journal.page.0000033", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2738|Dementia and Cognitive Impairment Research" ], [ "plos", "/Biology and life sciences/Biochemistry/Biomarkers" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Cell biology/Chromosome biology/Chromatin/Chromatin modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Developmental biology/Molecular development/Cytokines" ], [ "plos", "/Biology and life sciences/Developmental biology/Organism development/Aging" ], [ "plos", "/Biology and life sciences/Genetics/DNA/DNA modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Genetics/Epigenetics/Chromatin/Chromatin modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Genetics/Epigenetics/DNA modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Chromatin/Chromatin modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/DNA modification/DNA methylation" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Biology and life sciences/Immunology/Immunity" ], [ "plos", "/Biology and life sciences/Neuroscience/Cognitive neuroscience/Cognitive neurology/Cognitive impairment" ], [ "plos", "/Biology and life sciences/Neuroscience/Cognitive science/Cognitive neuroscience/Cognitive neurology/Cognitive impairment" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Cytokines" ], [ "plos", "/Biology and life sciences/Physiology/Physiological processes/Aging" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Medicine and health sciences/Immunology/Immunity" ], [ "plos", "/Medicine and health sciences/Medical conditions/Cerebrovascular diseases/Stroke" ], [ "plos", "/Medicine and health sciences/Neurology/Cerebrovascular diseases/Stroke" ], [ "plos", "/Medicine and health sciences/Neurology/Cognitive neurology/Cognitive impairment" ], [ "plos", "/Medicine and health sciences/Vascular medicine/Stroke" ] ], "openalex": "W7214309429", "pdf_url": "https://journals.plos.org/agingandhealth/article/file?id=10.1371/journal.page.0000033&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-25", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/c0aybzc7hbad1.ris", "sources": [ { "first_seen": "2026-10-30T12:17:43Z", "native_id": "10.1371/journal.page.0000033", "source": "plos", "url": "https://doi.org/10.1371/journal.page.0000033" } ], "subjects": [ { "field": "biology", "origin": "plos:genetics", "subfield": "genetics-genomics" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework", "title_text": "The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:43Z", "url": "https://research.draconitic.com/paper/c0aybzc7hbad1", "venue": "PLOS Aging and Health", "versions": [] }