Accelerated biological aging increases the risk of short- and long-term stroke prognosis in patients with ischemic stroke or TIA.

Background: Biological age (BA), an integrated measure of physiological aging, has a clear link to stroke. There is a paucity of long-term longitudinal studies about the association between accelerated biological age and stroke prognosis in patients with previous strokes, and the differences in the predictive ability of various BA indicators calculated from clinical biochemistry biomarkers for future stroke outcomes are still unknown. To evaluate the role of three accelerated BA indicators for short- and long-term prognosis of patients with ischemic stroke or transient ischemic attack (TIA), and to identify the most appropriate predictor.

Methods: This study included 7396 patients from the Third China National Stroke Registry (CNSR-III), a prospective national registry of patients with acute ischemic stroke or TIA between August 2015 and March 2018 in China. We constructed accelerated BA using three widely recognized algorithms: PhenoAge, Klemera-Doubal, and HD method. To ascertain the association of accelerated BA with the risk of short- and long-term stroke outcomes, a Cox or logistic regression model was conducted for the analysis. The net reclassification index and integrated discrimination improvement were used to evaluate the added model improvement ability of BA acceleration.

Findings: Compared to those with the lowest of PhenoAge acceleration, patients with the highest were more likely to have a higher risk of stroke (HR 1.98, 95% CI 1.49-2.63, P < 0.001), ischemic stroke (HR 1.88, 95% CI 1.41-2.53, P < 0.001), composite vascular events (HR 2.03, 95% CI 1.53-2.68, P < 0.001), all-cause death (HR 7.02, 95% CI 3.41-14.47, P < 0.001) and the modified Rankin scale of 3-6 (OR 2.55, 95% CI 2.05-3.16, P < 0.001) at three months, and the association observed within one year and five years was similar to that within three months. The risk of all stroke outcomes for HDAge was consistent with PhenoAge acceleration, but KDMAge acceleration was the same, except for stroke within one year (HR 1.24, 95% CI 1.00-1.53, P = 0.053). PhenoAge acceleration provided a better improvement in the model's predictive ability for stroke prognosis, compared to BA determined by other algorithms.

Interpretation: In this prospective cohort study, BA acceleration, particularly PhenoAge, may help identify stroke patients with risks of short- and long-term poor outcomes, potentially enabling subclinical prevention and early intervention.

Funding: This work was supported by grants from Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2019-I2M-5-029), the National Natural Science Foundation of China (U20A20358), Beijing Hospitals Authority Clinical Medicine Development of special funding support (ZLRK202312), the National Key R&D Program of China (No. 2022YFC3602500, 2022YFC3602505), Outstanding Young Talents Project of Capital Medical University (A2105), and Beijing High-Level Public Health Technical Personnel Construction Project (Discipline leader -03-12).