Journal Article Annotations
2023, 3rd Quarter
Annotations by Zach Harvanek, MD, PhD
The study authors found that individuals with bipolar disorder were biologically older than individuals without bipolar disorder after adjusting for age. This was true for those with bipolar who had never attempted suicide (1.19 year older than controls) and those with bipolar who had previously attempted suicide (2.83 years older than controls). This difference between those who had attempted suicide and those who had not was also significant. In a replication cohort with 95 individuals who have bipolar 1 disorder, those who had previously attempted suicide were again found to be biologically older than those who had not attempted. In general, these results remained significant after accounting for sex, body-mass index, smoking, ancestry, and age. The authors further analyzed specific components of the biological aging clock to suggest this effect could be mediated by plasminogen activator inhibitor 1, leptin, and smoking.
Strength and weaknesses:
Strengths of this study include the use of two independently-recruited cohorts, enhancing generalizability and reliability of findings. The authors also account for multiple covariables, though with multiple models their findings could be difficult to interpret. Weaknesses include that the analysis is cross-sectional and thus causality is unclear: Have the prior suicide attempts driven accelerated aging, or is accelerated aging predictive of suicide attempts? The sample size of each study is also relatively small, and the replication cohort lacked a comparison group of patients without bipolar disorder.
These findings suggest accelerated aging is associated with both bipolar disorder and suicide risk. Notably, lithium has previously been associated with extended lifespan (see the Q1 2023 annotation), though in this study did not find a direct relationship between medication use and accelerated aging. Future studies could investigate biological aging as a potential marker and/or target for bipolar treatment and suicide prevention. The benefits of treatment on aging outcomes remain speculative—for now.
In a prospective study of medically healthy, unmedicated depressed patients (n = 48), the authors identified that longer pre-treatment telomere length (associated with younger biological age) predicted a positive response to SSRI treatment after 8 weeks. Positive response was defined as an improvement of at least 50% in HDRS scores (n of responders = 10, n of non-responders = 22). ROC analysis of telomere length demonstrated an AUC of 78.6%. The authors went on to demonstrate that telomere length was associated with increased allostatic load and increased cardiometabolic risk scores. No significant relationships were found with telomerase activity and outcome variables.
Strength and weaknesses:
Strengths of this study include its prospective design with a priori hypotheses based on prior work; some of this work replicates those prior findings as well. The use of medication-free subjects also enhances the interpretability of their study, although it may limit the generalizability. Weaknesses include a relatively small sample size and the lack of follow-up after the 8 week time frame.
Measures of biological aging, such as telomere length, may be useful biomarkers to identify individuals who will respond to SSRI treatment, though further studies are needed to confirm these results and identify potential cut-off points.
In this study, the authors recruited 289 individuals who presented to the emergency department within 72 hours of experiencing trauma, collected blood samples to assess epigenetic age, and then followed subjects longitudinally to determine if they developed PTSD after 6 months. The authors identified accelerated biological age (as measured via GrimAge, an epigenetic clock) as predictive of increased risk for the development of PTSD, with those in the highest third of GrimAge having a 44% increased relative risk compared to those in the lowest third. Accelerated GrimAge predicted worse intrusive memories and nightmares though was not related to other symptom clusters. Accelerated GrimAge was also associated with reduced amygdala volume 2 weeks after the traumatic event in a subset of 63 patients who also had neuroimaging data.
Strength and weaknesses:
Strengths of this study include its prospective design, including the collection of data shortly after the traumatic event and follow-up for incident traumatic symptoms. The inclusion of neuroimaging data is also a strength, although it is unclear if these findings represent changes shortly after trauma or whether they reflect changes that were already present. Weaknesses include the lack of a control group, and the lack of a second timepoint measuring epigenetic aging.
These findings suggest that risk for the development of PTSD after traumatic events may be predicted by epigenetic aging. Future studies could further use GrimAge to identify of at-risk individuals and potentially predict outcomes after early intervention.