Accelerated Aging Predicts Earlier Onset of Ischemic Stroke: A Proteomic and Transcriptomic Investigation

The incidence of ischemic stroke in younger adults has risen worldwide. We investigated the clinical and molecular associations of accelerated aging in patients with ischemic stroke.

Ischemic stroke patients and community-dwelling healthy controls were recruited from the National University Hospital, Singapore, from January 2018 to December 2019. We developed models using Olink® Explore 1536 proteomic data from healthy individuals to estimate biological age, then applied them to stroke patients. Accelerated aging was defined as exceeding the 97.5th percentile of biological age variation in healthy controls. Next-generation RNA sequencing was performed to explore aging-related pathways in stroke patients. Proteomic analysis of 384 age-stratified healthy controls provided biological-age estimate (R2 =0.98, mean absolute error =0.55 years); this model was then applied to 679 stroke patients (mean chronological age 58.7 years, 72% men). Nearly 40% of these patients exhibited accelerated aging. Stroke occurred 8.9 years earlier in those with accelerated aging than in those without (mean 53.4 vs. 62.3 years). Moreover, the mean biological age of 100 patients increased from 54.1 to 55.9 years three months post-stroke (paired t-test, p<0.001). Among stroke patients younger than 50 years, each additional year by which biological age exceeded chronological age was associated with a 12.9% higher odds of stroke (adjusted odds ratio, 1.13; 95% CI, 1.07-1.20, p<0.001). RNA sequencing analysis revealed differential gene expression and enrichment of olfactory-signaling and sensory-perception pathways among patients with accelerated aging.

Accelerated aging is an independent risk factor for ischemic stroke, warranting further investigation into its mechanisms to guide targeted interventions.