Biological age acceleration is more prevalent in men than in women at time of spontaneous intracerebral hemorrhage

  1. Cristina Gallego-Fabrega
  2. Joan Jiménez-Balado
  3. Natalia Cullell
  4. Jara Cárcel-Márquez
  5. Elena Muiño
  6. Laia Llucià-Carol
  7. Jesús M. Martin-Campos
  8. Laia Mariné
  9. Paula. Villatoro-Gonzalez
  10. Paula Boldo
  11. Ana Aguilera-Simon
  12. Anna. Ramos-Pachon
  13. Pol. Camps-Renom
  14. Luis. Prats-Sanchez
  15. Jaume Roquer
  16. Joan Martí-Fabregas
  17. Jordi Jiménez-Conde
  18. Israel Fernández-Cadenas
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Abstract

Objective

Spontaneous intracerebral hemorrhage (ICH) occurs later in life in women compared to men. Although previous studies have demonstrated epigenetic age acceleration (EAA) differences in ischemic stroke (IS) patients - a measure of an individual’s biological aging -it remains unknown whether this sex dimorphism also applies to ICH patients.

Approach and Results

We joined two ICH cohorts (N= 200, 45% women: 76.8±13 years; 55% men: 67.9±14 years). DNAm levels were obtained from whole blood samples using Illumina EPIC array. We evaluated three age-predictor clocks (Horvath, Hannum and Zang-BLUP) and one health-status clock (Levine) and their respective EAA metrics including extrinsic EAA (EEAA) and intrinsic EAA (IEAA) measures. We compared aging measures between women and men, then performed an ICH-subtype stratification, a specificity analysis evaluating sex differences in non-stroke samples (N= 350, 54% women 60.8±8 years, men: 60.8±10 years) and replication of previous result in a new IS cohort (N= 657, 43% women 73.6±12 years, men: 70.1±11 years).

Women at time of ICH present lower EAA values than men (Horvath-EAA, p-value=1×10 -04 ; Hannum-EAA, p-value=8.1×10 -06 ; BLUP-EAA, p-value=4.4×10 -04 ) as well as lower extrinsic EAA values (Horvath-IEAA, p-value=3.1×10 -03 ; Hannum-IEAA, p-value=6.5×10 -04 ). These differences seemed to be driven by differences in deep-ICH patients. Non-ICH females have lower acceleration values (Hannum-EAA: -10,37) than non-ICH men (Hannum-EAA: -8,01), but the differences are smaller than in ICH cases (ICH-women Hannum-EAA: -9,26, ICH-men Hannum-EAA: -2,6). This pattern was consistent in the IS cohort, where women were chronologically older than men but had similar biological age and significantly lower epigenetic age acceleration across multiple measures (Horvath-EAA, p = 2.6×10 −3 ; Hannum-EAA, p = 7.1×10 −3 ; Horvath-IEAA, p = 1.6×10 −2 ; Hannum-IEAA, p = 4.5×10 −2 ).

Conclusion

This study shows that biological age difference between women and men are not exclusive of ischemic stroke but also observed in ICH.

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  1. Version published to 10.1101/2025.10.01.679916 on bioRxiv