Comment on “Association between biological aging and stroke and all-cause mortality: A population-based cross-sectional study and Mendelian randomization analysis”

Comment on "Association between biological aging and stroke and all-cause mortality: A population-based cross-sectional study and Mendelian randomization analysis" Dear Editor, We read the recent article, "Association between biological aging and stroke and all-cause mortality: A population-based cross-sectional study and Mendelian randomization analysis," with interest.Using NHANES 1999-2018 and bidirectional two-sample Mendelian randomization (MR), the study reports that higher frailty index (FI), phenotypic age, and Klemera-Doubal biological age (and related "accelerations") are associated with prevalent, self-reported stroke, and that higher biological aging measures are associated with higher all-cause mortality among stroke survivors.The report also suggests genetically predicted FI may have the most consistent association with stroke outcomes in MR analyses. 1he Methods define accelerated aging as a positive residual, yet "non-accelerated aging" is described using a threshold of " 025," which appears inconsistent with the stated definition and may affect exposure classification.In addition, several multivariable effect estimates for "acceleration" measures appear numerically identical to their corresponding "age" measures across adjusted models, despite differing crude estimates.Given that these results underpin the main conclusions, clarification (and, if needed, a corrected table with reproducible code or supplementary calculations) would materially strengthen confidence in the findings.Temporality, prevalence inference, and construct overlap.The NHANES component is cross-sectional and models stroke prevalence based on self-report, which is inherently vulnerable to reverse causation and survivorship bias.This is especially relevant for FI, where functional dependence and related deficits can reflect post-stroke consequences rather than premorbid vulnerability.Longitudinal evidence indicates that stroke is associated with an acute cognitive decrement and accelerated post-stroke decline, supporting the plausibility that stroke can itself worsen aging-related phenotypes and thereby inflate crosssectional associations. 2We suggest sensitivity analyses that (where possible) separate frailty deficits plausibly attributable to stroke-related disability, and that explicitly frame estimates as associations with prevalence rather than incident "risk."Practical guidance on frailty assessment in stroke services further supports the need to distinguish baseline frailty from stroke sequelae when translating these measures into clinical decisions. 3R interpretation and multiplicity.The evidentiary rule that an IVW p<0.05 may be interpreted as "positive" when other MR estimators are directionally consistent but non-significant could overstate evidence when testing multiple aging traits across multiple stroke outcomes.Transparent multiplicity handling (e.g., false discovery rate across all exposure-outcome pairs), along with core diagnostics (instrument strength, heterogeneity, pleiotropy, and directionality checks), would improve causal interpretation and clinical messaging. 4 These clarifications align with contemporary neurology perspectives that frailty is increasingly relevant to decision-making but requires careful measurement and interpretation. 5 This study addresses an important clinical question and highlights the potential relevance of biological aging measures in cerebrovascular disease.Addressing the reporting issues, strengthening the temporal interpretation, and tightening MR inference would improve interpretability and help readers translate these findings into practice and future prospective research.