Associations of stress and stress-related psychiatric disorders with GrimAge acceleration: review and suggestions for future work

The notion of biological aging as distinct from chronological aging has been of increasing interest in psychiatry, and many studies have explored associations of stress and psychiatric illness with accelerated biological aging. The epigenetic clocks are one avenue of this research, wherein biological age is estimated using DNA methylation data from specific CpG dinucleotide sites within the human genome. Many iterations of the epigenetic clocks have been developed, but the GrimAge clock continues to stand out for its ability to predict morbidity and mortality. Several studies have now explored associations of stress, PTSD, and MDD with GrimAge acceleration (GrimAA). While stress, PTSD, and MDD are distinct psychiatric entities, they may share common mechanisms underlying accelerated biological aging. Yet, no one has offered a review of the evidence on associations of stress and stress-related psychopathology with GrimAA. In this review, we identify nine publications on associations of stress, PTSD, and MDD with GrimAA. We find that results are mixed both within and across each of these exposures. However, we also find that analytic methods - and specifically, the choice of covariates - vary widely between studies. To address this, we draw upon popular methods from the field of clinical epidemiology to offer (1) a systematic framework for covariate selection, and (2) an approach to results reporting that facilitates analytic consensus. Although covariate selection will differ by the research question, we encourage researchers to consider adjustment for tobacco, alcohol use, physical activity, race, sex, adult socioeconomic status, medical comorbidity, and blood cell composition.

Automated summary

Psychiatry has shown increasing interest in the concept of biological aging, and research has explored the relationship between stress, psychiatric illness, and accelerated biological aging. Epigenetic clocks, specifically the GrimAge clock, have been used to estimate biological age based on DNA methylation data. Several studies have examined the associations between stress, PTSD, MDD, and GrimAge acceleration, but the results are mixed, possibly due to variations in analytic methods and covariate selection. To address this issue, a systematic framework for covariate selection and an approach to results reporting are proposed to improve analytic consensus.