Journal Article Annotations
2024, 2nd Quarter

Aging

Annotations by Zachary Harvanek, MD, PhD
July, 2024

Childhood adversity, accelerated GrimAge, and associated health consequences.
Accelerated epigenetic aging in alcohol dependence.
The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.

PUBLICATION #1 — Aging

Childhood adversity, accelerated GrimAge, and associated health consequences.

Zachary M Harvanek, Anastacia Y Kudinova, Samantha A Wong, Leslie Brick, Teresa E Daniels, Carmen Marsit, Amber Burt, Rajita Sinha, Audrey R Tyrka.

Abstract: J Behav Med. 2024 May 18. doi: 10.1007/s10865-024-00496-0. Online ahead of print.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

Annotation

The finding:
In two, independent cross-sectional cohorts of generally healthy adults, the authors found that early life stress was associated with accelerated epigenetic aging. This association was driven primarily by those who reported abuse (as opposed to neglect). Notably, in this population accelerated epigenetic aging was associated with insulin resistance in those with obesity, but not in those with a BMI of less than 25.

Strength and weaknesses:
Strengths of this study include the use of two, independently-recruited cohorts with similar measures, the use of multiple measures of early life stress, specifically the Childhood Experience of Care and Abuse (CECA) Questionnaire CECA and the Childhood Trauma Questionnaire (CTQ), and the use of generally healthy cohorts to avoid confounding from pre-existing medical conditions. Weaknesses include the cross-sectional nature of the study which limits the ability to draw causal inference, the reliance on retrospective reporting of early life stress, and the limited racial and ethnic diversity of the cohorts.

Relevance:
These findings suggest a connection between early life stress, obesity, and insulin resistance. Given the higher levels of accelerated aging and obesity in patients with childhood adversity, psychiatrists may want to consider using non-obesigenic medications in this patient population.

PUBLICATION #2 — Aging

Accelerated epigenetic aging in alcohol dependence.

Toshiyuki Shirai, Satoshi Okazaki, Ikuo Otsuka, Masao Miyachi, Takaki Tanifuji, Ryota Shindo, Shohei Okada, Haruka Minami, Tadasu Horai, Kentaro Mouri, Akitoyo Hishimoto.

Abstract: J Psychiatr Res. 2024 May:173:175-182. doi: 10.1016/j.jpsychires.2024.03.025. Epub 2024 Mar 23.

Alcohol dependence poses a global health threat associated with aging and reduced life expectancy. Recently, aging research through deoxyribonucleic acid (DNA) methylation has gained attention. New epigenetic clocks have been developed; however, no study has investigated GrimAge components, GrimAge2 components and DunedinPACE in patients with alcohol dependence. In this study, we aimed to perform epigenetic clock analysis to evaluate epigenetic age acceleration and DNA methylation-based age-predictive components in patients with alcohol dependence and controls. We utilized publicly available DNA methylation data (GSE98876) for our analysis. Additionally, we compared the values of the same items before and after the patients underwent a treatment program. The dataset comprised 23 controls and 24 patients. We observed that DunedinPACE accelerated more in patients with alcohol dependence. AgeAccelGrim and AgeAccelGrim2 decelerated more after the treatment program than before, and beta-2-microglobulin and Cystatin C decreased after the treatment program than before. These findings are crucial as they affect the cranial nerve area, potentially contributing to cognitive dysfunction and psychiatric symptoms in patients with alcohol dependence.

Annotation

The finding:
In an analysis of 24 patients with alcohol dependence who underwent a three-week alcohol treatment program and 23 controls, the authors found that GrimAge (both versions 1 and 2) and a DNA methylation estimate of telomere length were improved after the three-week treatment. The change in GrimAge was driven by specific components, including methylation measures of B2M and Cystatin C (measures of renal disfunction).

Strength and weaknesses:
Strengths of this study include a longitudinal design which includes before- and after-treatment measures of epigenetic aging, the use of a specific subpopulation of WBCs for increased signal (CD3+ cells), as well as robust correction for multiple comparison testing using the Bonferroni method. Weaknesses include the small sample size and lack of longer follow up periods.

Relevance:
This study suggests that, in patients with alcohol dependence, a significant decrease in alcohol use (via a 21-day program) is associated with decreased epigenetic aging. This study may serve as evidence to support the potential benefits of alcohol cessation in general and alcohol treatment programs in particular.

PUBLICATION #3 — Aging

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.

Julian Mutz, Win Lee Edwin Wong, Timothy R Powell, Allan H Young, Gavin S Dawe, Cathryn M Lewis.

Abstract: Geroscience. 2024 Mar 28. doi: 10.1007/s11357-024-01142-y. Online ahead of print.

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β = – 0.022, 95% CI – 0.081 to 0.037, p = 0.47), the total duration of use (β = – 0.005, 95% CI – 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β = – 0.018, 95% CI – 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.

Annotation

The finding:
In this observational study, 591 patients were included. The study participants in this investigation were individuals with documented lithium usage, and data on the duration of their lithium prescriptions was accessible. In addition, multiple measures of aging were evaluated for these participants. The sample included both individuals with bipolar illness (n = 248) and depression (n = 176). This study found no effect of duration of lithium treatment on telomere length, frailty, a metabolomic marker of aging, or all-cause mortality.

Strength and weaknesses:
Strengths of this study include information on duration of lithium use, the use of multiple measures of aging (including frailty, biomarkers such as telomere length, and mortality), and adjustment for confounding factors including chronologic age and sex. The most important limitation of the study is the lack of comparison to a non-lithium-using control group, which limits the ability to draw inference about the effect of lithium versus no lithium. The study was also primarily limited to individuals between 40-69 years of age due to the UK Biobank recruitment method, and the use of prescription data to infer adherence.

Relevance:
Prior work has suggested that lithium may reduce several markers of aging as well as overall mortality. This work would seem to be in contrast to that, although the focus on duration of lithium use (as opposed to comparing lithium use to not using lithium) is distinct from many other studies. In general, this does demonstrate further need for studying the potential anti-aging effects of lithium.