Abstract
Age and stroke severity are the main mortality predictors after ischemic stroke. However, chronological age and biological age are not exactly concordant. Age-related changes in DNA methylation in multiple CpG sites across the genome can be used to estimate biological age, which is influenced by lifestyle, environmental factors, and genetic variation. We analyzed the impact of biological age on 3-month mortality in ischemic stroke. We assessed 594 patients with acute ischemic stroke in a cohort from Hospital del Mar (Barcelona) and validated the results in an independent cohort. Demographic and clinical data, including chronological age, vascular risk factors, initial stroke severity (NIHSS score), recanalization treatment, and previous modified Rankin scale were registered. Biological age was estimated with an algorithm based on DNA methylation in 71 CpGs. Biological age was predictive of 3-month mortality (p = 0.041; OR = 1.05, 95% CI 1.00–1.10), independently of NIHSS score, chronological age, TOAST, vascular risk factors, and blood cell composition. Stratified by TOAST classification, biological age was associated with mortality only in large-artery atherosclerosis etiology (p = 0.004; OR = 1.14, 95% CI 1.04–1.25). As estimated by DNA methylation, biological age is an independent predictor of 3-month mortality in ischemic stroke regardless of chronological age, NIHSS, previous modified Rankin scale, and vascular risk factors.
Highlights
After an ischemic stroke (IS), determining the individual patient’s risk of mortality at hospital admission has great clinical relevance and provides critical information for patients and their families[1,2,3,4]
We previously reported that IS patients are biologically older, than controls of the same chronological age (c-Age) and that biological age (b-Age) is a better predictor of 3-month outcome[11,12]
We report that biological aging, an epigenetic biomarker estimated from DNA methylation (DNAm) values, better predicts mortality at 3 months after an IS event than chronological aging
Summary
After an ischemic stroke (IS), determining the individual patient’s risk of mortality at hospital admission has great clinical relevance and provides critical information for patients and their families[1,2,3,4]. DNA methylation (DNAm) is an epigenetic mechanism regulating higher-order DNA structure and gene expression. It is a heritable and reversible addition of a methyl group to the 5-carbon position of cytosine in a cytosine-phosphate-guanine (CpG) context, associated with gene silencing[5]. The difference between chronological and methylation-predicted age, defined as average age acceleration, can be used to determine whether the DNAm age, called epigenetic age or biological age (b-Age), is consistently higher or lower than expected. A recent meta-analysis of 13 cohorts found that epigenetic age acceleration predicts all-cause mortality, independent of c-Age and even after adjusting for traditional risk factors[13]. The aim of our study was to assess the b-Age contribution to IS mortality at 3 months and to stratify the analysis by stroke subtypes
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