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Background Biological aging may occur at different rates than chronological aging due to genetic, social, and environmental factors. DNA methylation (DNAm) age is thought to be a reliable measure of accelerated biological aging which has been linked to an array of poor health outcomes. Given the importance of chronological age in recovery following aneurysmal subarachnoid hemorrhage (aSAH), a type of stroke, DNAm age may also be an important biomarker of outcomes, further improving predictive models. Cerebrospinal fluid (CSF) is a unique tissue representing the local central nervous system environment post-aSAH. However, the validity of CSF DNAm age is unknown, and it is unclear which epigenetic clock is ideal to compute CSF DNAm age, particularly given changes in cell type heterogeneity (CTH) during the acute recovery period. Further, the stability of DNAm age post-aSAH, specifically, has not been examined and may improve our understanding of patient recovery post-aSAH. Therefore, the purpose of this study was to characterize CSF DNAm age over 14 days post-aSAH using four epigenetic clocks. Results Genome-wide DNAm data were available for two tissues: (1) CSF for  N  = 273 participants with serial sampling over 14 days post-aSAH ( N =  850 samples) and (2) blood for a subset of  n  = 72 participants at one time point post-aSAH. DNAm age was calculated using the Horvath, Hannum, Levine, and “Improved Precision” (Zhang) epigenetic clocks. “Age acceleration” was computed as the residuals of DNAm age regressed on chronological age both with and without correcting for CTH. Using scatterplots, Pearson correlations, and group-based trajectory analysis, we examined the relationships between CSF DNAm age and chronological age, the concordance between DNAm ages calculated from CSF versus blood, and the stability (i.e., trajectories) of CSF DNAm age acceleration over time during recovery from aSAH. We observed moderate to strong correlations between CSF DNAm age and chronological age ( R  = 0.66 [Levine] to  R  = 0.97 [Zhang]), moderate to strong correlations between DNAm age in CSF versus blood ( R  = 0.69 [Levine] to  R  = 0.98 [Zhang]), and stable CSF age acceleration trajectories over 14 days post-aSAH in the Horvath and Zhang clocks (unadjusted for CTH), as well as the Hannum clock (adjusted for CTH). Conclusions CSF DNAm age was generally stable post-aSAH. Although correlated, CSF DNAm age differs from blood DNAm age in the Horvath, Hannum, and Levine clocks, but not in the Zhang clock. Taken together, our results suggest that, of the clocks examined here, the Zhang clock is the most robust to CTH and is recommended for use in complex tissues such as CSF.

Characterization of cerebrospinal fluid DNA methylation age during the acute recovery period following aneurysmal subarachnoid hemorrhage