The impact of adverse childhood experiences on DNA methylation age: a systematic review and meta-analysis.

The systematic review identified 27 eligible observational studies from 1036 identified through comprehensive screening of the literature.

• 1036 studies were initially identified through literature screening
• 27 studies met eligibility criteria for inclusion
• Studies examined the relationship between cumulative ACE exposure and epigenetic age acceleration (EAA) in adults
• Studies involved more female participants, with a median of 56.6% female across included studies

Meta-analyses found no significant association between cumulative ACE exposure and epigenetic age acceleration using first-generation epigenetic clocks.

• Meta-analyses were conducted on 6 studies using cumulative ACE exposure and standardised regression coefficients
• Horvath clock: β = -0.03, 95% CI -0.15 to 0.09
• Hannum clock: β = -0.09, 95% CI -0.41 to 0.23
• Both confidence intervals spanned zero, indicating non-significant associations

Meta-analyses found no significant association between cumulative ACE exposure and epigenetic age acceleration using second-generation epigenetic clocks.

• Both PhenoAge and GrimAge clocks yielded β = 0.21
• Both 95% confidence intervals spanned zero, indicating non-significant associations
• PhenoAge and GrimAge were among the most frequently used clocks across included studies
• Horvath, GrimAge, and PhenoAge were the most frequently employed epigenetic clocks across studies

The included studies employed heterogeneous methodologies and produced mixed findings, particularly for individual ACEs and third-generation clocks.

• Narrative synthesis was used for studies that could not be included in the meta-analyses
• Mixed findings were particularly noted for individual ACEs rather than cumulative ACE exposure
• Third-generation clocks such as DunedinPACE showed heterogeneous findings
• Studies employed a range of different epigenetic clocks, contributing to methodological heterogeneity

Most included studies were rated as having some concerns regarding risk of bias, primarily due to a lack of adjustment for key covariates.

• Risk of bias was assessed using the ROBINS-E tool
• The primary source of bias concern was a lack of adjustment for key covariates
• Most studies, rather than a minority, were rated as having some concerns
• This limitation in covariate adjustment was identified as a key methodological gap across the literature

The authors concluded that while ACEs may influence biological aging, current evidence does not support a robust or consistent association with epigenetic age acceleration.

• The review identified a need for more consistent methodologies in future research
• Findings suggest the relationship between ACEs and EAA is not definitively established
• ACEs such as abuse and neglect are associated with poor health in adulthood, with EAA proposed as one biological mechanism
• Understanding EAA as a pathway could help identify links between early life stress and increased risk of morbidity and mortality