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The influence of epigenetic biological age on key complications and outcomes in aneurysmal subarachnoid haemorrhage
  1. Adrià Macias-Gómez1,2,
  2. Joan Jiménez-Balado2,
  3. Isabel Fernández‑Pérez1,2,
  4. Antoni Suárez‑Pérez1,2,
  5. Marta Vallverdú-Prats2,
  6. Leopoldo Guimaraens3,
  7. Elio Vivas3,
  8. Jesus Saldaña3,
  9. Eva Giralt-Steinhauer1,2,
  10. Daniel Guisado-Alonso1,2,
  11. Gloria Villalba4,5,
  12. Maria-Pilar Gracia5,6,
  13. Manel Esteller7,8,
  14. Ana Rodriguez-Campello1,2,5,
  15. Jordi Jiménez-Conde1,2,5,
  16. Angel Ois1,2,5,
  17. Elisa Cuadrado-Godia1,2,5
  1. 1Neurology Department, Hospital del Mar, Barcelona, Catalunya, Spain
  2. 2Neurovascular Research Group, Hospital del Mar Medical Research Institute, Barcelona, Catalunya, Spain
  3. 3J.J. Merland of Therapeutic Neuroangiography, Hospital del Mar, Barcelona, Catalunya, Spain
  4. 4Neurosurgery Department, Hospital del Mar, Barcelona, Catalunya, Spain
  5. 5Pompeu Fabra University, Barcelona, Catalunya, Spain
  6. 6Intensive Care Department, Hospital del Mar, Barcelona, Catalunya, Spain
  7. 7Cancer Epigenetics Group, Research Institute Against Leukemia Josep Carreras, Badalona, Catalunya, Spain
  8. 8Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain
  1. Correspondence to Dr Joan Jiménez-Balado; jjimenez3{at}


Background We aimed to investigate the association between DNA-methylation biological age (B-age) calculated as age acceleration (ageAcc) and key aneurysmal subarachnoid haemorrhage (aSAH) complications such as vasospasm, delayed cerebral ischaemia (DCI), poor outcome, and mortality.

Methods We conducted a prospective study involving 277 patients with aSAH. B-age was determined in whole blood samples using five epigenetic clocks: Hannum’s, Horvath’s, Levine’s and both versions of Zhang’s clocks. Age acceleration was calculated as the residual obtained from regressing out the effect of C-age on the mismatch between C-age and B-age. We then tested the association between ageAcc and vasospasm, DCI and 12-month poor outcome (mRS 3–5) and mortality using linear regression models adjusted for confounders.

Results Average C-age was 55.0 years, with 66.8% being female. Vasospasm occurred in 143 cases (51.6%), DCI in 70 (25.3%) and poor outcomes in 99 (35.7%), with a mortality rate of 20.6%. Lower ageAcc was linked to vasospasm in Horvath’s and Levine’s clocks, whereas increased ageAcc was associated with 12-month mortality in Hannum’s clock. No significant differences in ageAcc were found for DCI or poor outcome at 12 months with other clocks.

Conclusions Our study indicates that B-age is independently associated with vasospasm and 12-month mortality in patients with aSAH. These findings underscore the potential role of epigenetics in understanding the pathophysiology of aSAH-related complications and outcomes.


Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • X @NEUVAS1

  • AO and EC-G contributed equally.

  • Correction notice Since this article first published, the acknowledgements statement has been updated.

  • Contributors AM-G, EC-G, JJ-B and AO were involved in the conception and design of the study, interpretation of data and in the writing of the manuscript. JJ-B and AM-G performed the statistical analysis. All authors interpreted the data, reviewed the manuscript and approved the final version. AO and EC-G are joint last authors. EC-G is responsible for the overall content of the study as guarantor.

  • Funding This work was supported in part by Spain’s Ministry of Health (Instituto de Salud Carlos III, Fondos FEDER, RICORS-ICTUS (RD21/0006/0021) and P19/00011). Sara Borrell program, funded by Instituto de Salud Carlos III (CD22/00001, J.J.B.).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.