The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework
4 affiliations
- 1Department of Epidemiology, College of Public Health, Health Professions and College of Medicine, University of Florida, Gainesville, Florida, United States of America
- 2The Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, United States of America
- 3Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, United States of America
- 4Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
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.
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BibTeX
@article{waziry2026role,
title = {{The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework}},
author = {Reem Waziry and Caleb H. Miles and Olajide Williams and Henning Tiemeier},
journal = {PLOS Aging and Health},
year = {2026},
month = sep,
doi = {10.1371/journal.page.0000033},
url = {https://doi.org/10.1371/journal.page.0000033},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The role of DNA methylation-based biological aging, inflammation and immunity in post-stroke cognition: A unified causal framework
AU - Reem Waziry
AU - Caleb H. Miles
AU - Olajide Williams
AU - Henning Tiemeier
PY - 2026
DA - 2026/09/25
JO - PLOS Aging and Health
DO - 10.1371/journal.page.0000033
UR - https://doi.org/10.1371/journal.page.0000033
AB - 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.
SN - 3070-801X
ER -