Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men

Abstract

Background: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. Results: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=−0.64, men=1.24, P =1.34×10 -2 ); the same tendency was observed in the second cohort (women=−0.57, men=0.79, P =0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA ( P <0.05), belonging to the immune effector process ( P =1.54×10 -6 ) and platelet degranulation ( P <8.74×10 -6 ) pathways. Conclusions: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Ischaemic stroke patients present sex differences in gut microbiota

“…The reduction in species richness correlates with a worse outcome after IS in both human and animal models [30,31], possibly due to the decrease in the relative abundance of common core bacteria [30]. This is in agreement with the fact that women have a less favourable outcome after stroke than men [4]. We also found increased levels of Fusobacteria, Fusobacteriia, Proteobacteria and Verrucomicrobia, Fusobacteria are part of the dominant phyla of the gut microbiota [33].…”

Epigenetic mechanisms and potential therapeutic targets in stroke

“…[49][50][51] Furthermore, additional profiling studies showed that biological age (DNAm age), which is measured by circulating levels 5mC, can predict stroke risk, outcome, and recurrence more accurately than chronological age. [52][53][54][55][56] Thus, these studies collectively indicate that blood levels of methylated DNA may serve as a biomarker for the diagnosis, prognosis and treatment of stroke.…”

“…In particular, both DNAm age and methylation of SLC6A4 hold promise as biomarkers for stroke risk, recurrence, and outcome. [46][47][48][52][53][54][55][56] The current evidence indicates that epigenetic modulators have tremendous potential as biomarkers for both injury and response to therapy.…”

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

“…The DNAm age of IS patients is higher than their chronological age and that for matched controls [ 169 ]. DNAm age is also a better predictor of IS mortality [ 170 ]. More recently DNAm age differences between men and women, at the time of stroke onset, have been reported [ 170 ].…”

“…DNAm age is also a better predictor of IS mortality [ 170 ]. More recently DNAm age differences between men and women, at the time of stroke onset, have been reported [ 170 ].…”