The role of DNA methylation in the life course and age acceleration

Worldwide, ageing represents a major concern. Indeed, ageing is not only characterized by the accumulation of cellular or molecular damage over time and the decrease of physiological capacities, but it induces a higher health care burden, putting considerable pressure on public finances. Early life adversity (ELA) regroups different types of exposure all influencing individual ageing. The ELA label refers to socio-economic status, emotional and environmental exposures. As demonstrated in the Developmental Origins of Health and Diseases (DOHaD) concept, the most sensitive period of life covers the time between conception and age 2 where ELA is mainly occurring. Nonetheless, from conception to adulthood remains a period when ELA can occur. As life circumstances directly interact with biological processes, in this thesis I considered how socioeconomic stress as well as early maternal experience can be perceived by their offspring and how this may have epigenomic effects. Following the DOHaD concept, we used the Avon Longitudinal Parents and Children (ALSPAC) cohort to investigate how maternal trauma can affect their child’s epigenomes as well as the epigenetic ageing process. Here, we used different approaches to investigate this mother-child association. Firstly, the use of epigenetic clocks (EC) using DNA methylation pattern and considered as an accurate age biomarker, allowed us to demonstrate that child ageing is not associated with maternal trauma exposure. Secondly, the epigenome wide association study (EWAS) approach investigated whether the ageing process is associated to underlying biological mechanisms. Our EWAS models highlighted that maternal experience induces epigenetic imprints, for example in DNA methylation (DNAm), in their children remaining over years. Additionally, we demonstrated that those imprinted marks are associated with biological pathways such as Parkinson disease or oxidative phosphorylation pathways. Within those pathways of interest, we also observed that associated genes such as COX7C known to be associated with ageing were up regulated. On the contrary other genes were down regulated. Finally, we shed into light that mothers possess “directing CpGs” mainly associated with imprinted child’s DNAm, suggesting that an epigenetic transmission mechanism took place. Here, in the ALAC project, we answered to three key points of maternal-child association: 1) the in-utero transmission from the individual’s mother, 2) the effects of individual life events and statuses prior to the measurement of the epigenetic clock, and 3) changes evaluation in the EC within the same individual as well as the association between levels and changes in the clock between mother and child

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

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

A Holistic View of the Goto-Kakizaki Rat Immune System: Decreased Circulating Immune Markers in Non- Obese Type 2 Diabetes

Type-2 diabetes is a complex disorder that is now considered to have an immune component, with functional impairments in many immune cell types. Type-2 diabetes is often accompanied by comorbid obesity, which is associated with low grade inflammation. However,the immune status in Type-2 diabetes independent of obesity remains unclear. Goto-Kakizaki rats are a non-obese Type-2 diabetes model. The limited evidence available suggests that Goto-Kakizaki rats have a pro-inflammatory immune profile in pancreatic islets. Here we present a detailed overview of the adult Goto-Kakizaki rat immune system. Three converging lines of evidence: fewer pro-inflammatory cells, lower levels of circulating pro-inflammatory cytokines, and a clear downregulation of pro-inflammatory signalling in liver, muscle and adipose tissues indicate a limited pro-inflammatory baseline immune profile outside the pancreas. As Type-2 diabetes is frequently associated with obesity and adipocyte-released inflammatory mediators, the pro-inflammatory milieu seems not due to Type-2 diabetes per se; although this overall reduction of immune markers suggests marked immune dysfunction in Goto-Kakizaki rats. Copyright © 2022 Seal, Henry, Pajot, Holuka, Bailbé, Movassat, Darnaudéry and Turner.Diabète maternel et vulnérabilité neuropsychiatrique chez la descendance : rôle de la méthylation de l'AD

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

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

Developmental epigenomic effects of maternal financial problems.

peer reviewedEarly-life adversity as neglect or low socioeconomic status is associated with negative physical/mental health outcomes and plays an important role in health trajectories through life. The early-life environment has been shown to be encoded as changes in epigenetic markers that are retained for many years.We investigated the effect of maternal major financial problems (MFP) and material deprivation (MD) on their children's epigenome in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Epigenetic aging, measured with epigenetic clocks, was weakly accelerated with increased MFP. In subsequent EWAS, MFP, and MD showed strong, independent programing effects on children's genomes. MFP in the period from birth to age seven was associated with genome-wide epigenetic modifications on children's genome visible at age 7 and partially remaining at age 15.These results support the hypothesis that physiological processes at least partially explain associations between early-life adversity and health problems later in life. Both maternal stressors (MFP/MD) had similar effects on biological pathways, providing preliminary evidence for the mechanisms underlying the effects of low socioeconomic status in early life and disease outcomes later in life. Understanding these associations is essential to explain disease susceptibility, overall life trajectories and the transition from health to disease

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19

Methylation of serotonin regulating genes in cord blood cells: association with maternal metabolic parameters and correlation with methylation in peripheral blood cells during childhood and adolescence

Abstract Background Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence

The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood

There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring’s cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood