Children’s internalizing behavior development is heterogeneously associated with the pace of epigenetic aging

in Biological Psychology (2023), 176

Background: Internalizing behaviors are an indicator of children’s psychological and emotional development, predicting future mental disorders. Recent studies have identified associations between DNA ... [more ▼]

Background: Internalizing behaviors are an indicator of children’s psychological and emotional development, predicting future mental disorders. Recent studies have identified associations between DNA methylation (DNAm) and internalizing behaviors. This prospective study aimed at exploring the associations between pace of biological aging and the developmental trajectories of internalizing behaviors. Methods: Participants were children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N=974). Measures of DNA methylation were collected at birth, age 7 and ages 15-17. The pace of aging was estimated using the DunedinPoAm algorithm (PoAm). Internalizing behaviors reported by caregivers between ages 4 and 16 using the Strengths and Difficulties Questionnaire. To explore heterogeneity in the association between PoAm and internalizing behaviors we use Poisson quantile regression in cross-section heterogeneity and longitudinal latent class analysis over the childhood and adolescence. Results: Internalizing behavior trajectories were identified: low-risk, childhood limited, late onset and early onset (persistent). Accelerated aging at birth was negatively associated with internalizing behaviors in early childhood but positively correlated during adolescence. Higher PoAm at birth increased chance of low-risk profile, while decreasing likelihood of childhood limited trajectory. PoAm at age 15 was negatively associated with childhood limited profile and positively linked to late onset trajectories. Associations were larger at higher values of internalizing symptoms. Conclusions: The heterogeneity in the association between biological age acceleration and internalizing behaviors suggests a complex dynamic relationship, particularly in children with high or increased risk of adverse mental health outcomes. [less ▲]

Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity.

in Journal of clinical medicine (2021), 10(10),

Asymptomatic individuals, called "silent spreaders" spread SARS-CoV-2 efficiently and have complicated control of the ongoing COVID-19 pandemic. As seen in previous influenza pandemics, socioeconomic and ... [more ▼]

Asymptomatic individuals, called "silent spreaders" spread SARS-CoV-2 efficiently and have complicated control of the ongoing COVID-19 pandemic. As seen in previous influenza pandemics, socioeconomic and life-trajectory factors are important in disease progression and outcome. The demographics of the asymptomatic SARS-CoV-2 carriers are unknown. We used the CON-VINCE cohort of healthy, asymptomatic, and oligosymptomatic individuals that is statistically representative of the overall population of Luxembourg for age, gender, and residency to characterise this population. Gender (male), not smoking, and exposure to early-life or adult traumatic experiences increased the risk of IgA seropositivity, and the risk associated with early-life exposure was a dose-dependent metric, while some other known comorbidities of active COVID-19 do not impact it. As prior exposure to adversity is associated with negative psychobiological reactions to external stressors, we recorded psychological wellbeing during the study period. Exposure to traumatic events or concurrent autoimmune or rheumatic disease were associated with a worse evolution of anxiety and depressive symptoms throughout the lockdown period. The unique demographic profile of the "silent spreaders" highlights the role that the early-life period plays in determining our lifelong health trajectory and provides evidence that the developmental origins of health and disease is applicable to infectious diseases. [less ▲]

Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

in Cell Metabolism (2020), 31(5), 920--9367

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for ... [more ▼]

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality. [less ▲]

Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment

in International Journal of Molecular Sciences (2020), 21

The role of twins in research is evolving as we move further into the post-genomic era. With the re-definition of what a gene is, it is becoming clear that biological family members who share a specific ... [more ▼]

The role of twins in research is evolving as we move further into the post-genomic era. With the re-definition of what a gene is, it is becoming clear that biological family members who share a specific genetic variant may well not have a similar risk for future disease. This has somewhat invalidated the prior rationale for twin studies. Case co-twin study designs, however, are slowly emerging as the ideal tool to identify both environmentally induced epigenetic marks and epigenetic disease-associated processes. Here, we propose that twin lives are not as identical as commonly assumed and that the case co-twin study design can be used to investigate the effects of the adult social environment. We present the elements in the (social) environment that are likely to affect the epigenome and measures in which twins may diverge. Using data from the German TwinLife registry, we confirm divergence in both the events that occur and the salience for the individual start as early as age 11. Case co-twin studies allow for the exploitation of these divergences, permitting the investigation of the role of not only the adult social environment, but also the salience of an event or environment for the individual, in determining lifelong health trajectories. In cases like social adversity where it is clearly not possible to perform a randomised-controlled trial, we propose that the case cotwin study design is the most rigorous manner with which to investigate epigenetic mechanisms encoding environmental exposure. The role of the case co-twin design will continue to evolve, as we argue that it will permit causal inference from observational data. [less ▲]

Transcriptional control of the human glucocorticoid receptor: Identification and analysis of alternative promoter regions

in Human Genetics (2011), 129(5), 533-543