Journal Article Annotations
2025, 1st Quarter

Aging

Annotations by Zachary Harvanek, MD, PhD
March, 2025

Epigenetic age across development in children and adolescents with ADHD.
Sexual minority stress and epigenetic aging.

PUBLICATION #1 — Aging

Epigenetic age across development in children and adolescents with ADHD.

Jo Wrigglesworth, Peter D Fransquet, Peter Ryabinin, Michael A Mooney, Jeffrey M Craig, Tim J Silk.

Abstract: Psychiatry Res. 2025 Mar:345:116373. doi: 10.1016/j.psychres.2025.116373. Epub 2025 Jan 20.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, though symptoms vary both within and between people in the population. We aimed to investigate trajectories of individual biological aging through the change in residuals of DNA methylation age estimates (EpiAge) regressed on chronological age (EpiAge Gap) in children and adolescents with and without ADHD.

Methods:
Three well-established epigenetic clocks (PedBE, Horvath, and Skin & blood) were used to estimate EpiAge in 293 saliva samples from 169 participants (91 with ADHD symptoms) from the Neuroimaging of the Children’s Attention Project (NICAP). Participants attended single (cross-sectional sample, n = 75) or multiple (2-3) waves of assessment (longitudinal sample, n = 94). We compared EpiAge Gap between ADHD and control groups cross-sectionally and longitudinally, and replicated these findings in a second pediatric cohort from the Oregon ADHD-1000 cohort.

Results:
Across all three clocks, EpiAge Gap was comparable between ADHD and controls from the cross-sectional sample, and was a null finding for our longitudinal analysis of change in EpiAge Gap, after FDR correction (pFDR=0.24). Both cross-sectional and longitudinal findings were consistent in the replication cohort.

Conclusion:
This study found no strong evidence of differential epigenetic aging in developing children and adolescents with or without ADHD. Larger cohort studies, which utilize estimates over a prolonged duration, crossing both early and later developmental periods, would further our understanding of biological age in ADHD.

Annotation

The finding:
In this study, which includes both cross-sectional and longitudinal analyses as well as a replication cohort, the authors find that children (~9-11 years old) with ADHD show minimal differences in epigenetic age compared to children without ADHD. Using three different epigenetic clocks, the authors find that epigenetic age is similar in individuals with and without ADHD. Longitudinal analyses demonstrated a nominally significant effect of ADHD on age over time in one of the three epigenetic clocks (potentially suggesting ADHD leads to increasing epigenetic age over time), though this did not withstand adjustment for multiple corrections, and no significant effect was seen in the replication cohort. These conclusions were not altered when considering either symptom persistence/remission or medication use.

Strength and weaknesses:
This study has significant strengths, including the use of two separate cohorts (including a longitudinal component), strong statistical considerations including adjustment for multiple comparisons, and the use of an epigenetic clock that is specific to pediatric populations (PedBE). Limitations of this study include the use of saliva samples for epigenetic age calculation, which show only moderate correlation with blood-based calculations. However, it is worth noting that saliva samples are more commonly used in children, so this is in line with the literature. Overall, the epigenetic clocks are less-validated in pediatric populations, which likely explains the use of a limited number of clocks (only 3 clocks were examined). Overall sample sizes were also relatively modest, which may contribute to the null findings.

Relevance:
These null findings suggest that children with ADHD do not show accelerated aging compared to children without ADHD. However, we know that individuals with ADHD have higher morbidity and mortality in adulthood, and other work has demonstrated effects of ADHD on aging in adulthood are mediated by smoking, education, income, depression, and obesity. Thus, this work would support a model where ADHD increases mortality and accelerates aging as a result of its symptomatology and associated effects, not an inherent result of the disorder.

PUBLICATION #2 — Aging

Sexual minority stress and epigenetic aging.

Lisa M Christian, Stephanie Wilson, Annelise A Madison, Claire M Kamp Dush, Thomas W McDade, Juan Peng, Rebecca R Andridge, Ethan Morgan, Wendy Manning, Steve W Cole.

Abstract: Brain Behav Immun. 2025 Jan 31:126:24-29. doi: 10.1016/j.bbi.2025.01.022. Online ahead of print.

Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ + ) individuals have poorer mental and physical health than heterosexuals, and bisexuals fare worse than individuals who identify as lesbian and gay. However, data on stress biology among sexual minorities are critically insufficient. The current pilot study utilized data from 32 bisexual women – a subset of the National Couples’ Health and Time Study – who completed questionnaires and provided blood samples to index biological aging from DNA methylation data (DunedinPACE, GrimAge2). The mean DunedinPACE score was 1.13 (SD = 0.18), which outpaced chronological aging by 13 % (p < 0.001). Likewise, bisexual women in this sample were, on average, 8.67 (SD = 5.96) years older biologically per GrimAge2 as compared to their chronological age. In covariate adjusted models, those reporting greater internalized homonegativity exhibited significantly greater epigenetic age acceleration (GrimAge2: p = 0.01; DunedinPACE: p = 0.041). Those who reported more frequent anti-bisexual experiences also showed accelerated GrimAge2 (p = 0.023). In contrast, those who reported stronger identity centrality (p = 0.017), stronger identity affirmation (p = 0.029), and more friend support (p = 0.018) – a critical type of support for LGBTQ + individuals – had slower GrimAge2. Depressive symptoms, anxiety and loneliness were not associated with GrimAge2 or DunedinPACE. Results suggest that bisexual women are at risk for accelerated aging, and those who have less internal and external affirmation of their sexual identity may be most at risk.

Annotation

The finding:
This pilot study of 32 bisexual women from the National Couples’ Health and Time Study found that they have accelerated aging as measured by both GrimAge V2 and DunedinPACE. GrimAge suggested they were biologically 8.6 years older than their chronologic age, and DunedinPACE suggests they age 13% faster than average. They go on to find that experiences of discrimination, internal homonegativity, and psychological aggression were associated with accelerated aging, and identity centrality and affirmation and social support were protective against these effects.

Strength and weaknesses:
This study has multiple strengths, including its use of specific scales designed to assess discrimination against LGBTQ+ individuals in general, as well as bisexual individuals in particular. The study uses two newer clocks (GrimAge V2 and DunedinPACE), which were trained to predict morbidity and mortality, and the authors included multiple other covariates including smoking, BMI, and health conditions. The inclusion of resilience factors (instead of solely risk factors) is another strength to the study. As a pilot study, the sample size is quite small and thus power is a limitation. Other important limitations include the lack of a control group, which is particularly important given the analytic method. They appeared to use absolute differences between epigenetic age and chronologic age (as opposed to residuals) to calculate age acceleration. This was likely done because the average age acceleration of the population when using residuals would necessarily be 0, and thus they could not have asked whether there is age acceleration in bisexual women without a control group using this method. As there can be bias in epigenetic clock calculations when using this method, without a control group their conclusions regarding age acceleration in bisexual women are questionable, though understandable given this is a pilot study. Notably, this should not significantly impact assessments of resilience factors and risk factors.

Relevance:
This study, while small, provides evidence that psychosocial factors are important predictors of healthy aging in bisexual women. It specifically suggests that internalized homonegativity, anti-bisexual experiences, and partner psychological aggression are associated with worse health outcomes, whereas identify affirmation and friend support may be associated with better outcomes. This should serve to inform providers of psychotherapeutic approaches toward bisexual women regarding intervention targets that may best support healthy aging.