The role of the exposome in biological ageing and appetite regulation across youth - The relation of the external exposome with telomeres and appetite hormones

Abstract

Noncommunicable diseases (NCDs) are chronic conditions that are not directly transmissible between individuals (e.g. cancers, cardiovascular diseases, obesity, diabetes type 2). These diseases represent a major global health burden as they significantly contribute to mortality worldwide, causing 41 million deaths each year. NCDs emerge from a complex interplay between the individual’s genetic predisposition, surrounding environment (e.g. work and living conditions) and personal lifestyle choices (e.g. smoking, diet, physical activity). However, the exact underlying mechanisms remain to be explored. While genetic makeup is fixed, environmental and lifestyle factors are modifiable, offering opportunities for intervention. To address these modifiable contributors, the concept of the exposome has been developed, encompassing the totality of environmental exposures throughout an individual's life, starting from conception. While previous research has largely focused on the effects of single exposures or lifestyle factors on disease development, the exposome opens opportunities for understanding the interplay between exposures, their combined effects, and the underlying mechanisms which are crucial for effective prevention. Although most research has focused on adults’ lifestyle and exposures, early life may represent a critical period for the onset of NCDs, underscoring the need to investigate early-life mechanisms and exposures.

This dissertation aims to tackle these knowledge gaps by focusing on two potential underlying mechanisms (biological ageing and appetite regulation) through which the exposome may contribute to the early-life development of NCDs using population-based research. As many NCDs are linked with ageing, this dissertation investigates the link between the exposome and telomere attrition, a biomarker for biological ageing. Shorter telomeres have been linked to several NCDs, providing valuable insight into early biological effects and offering an ideal model to study the exposome's impact on ageing from early life onward. The second focus of this dissertation is on exploring underlying mechanisms of obesity, which is not only an NCD in itself but also a significant risk factor for the development of other NCDs, effectively acting as a double burden. Since obesity is often linked to increased appetite and impaired appetite hormone levels, this work explores appetite regulation as an underlying mechanism. It pioneers research concerning the exposome's impact on appetite-regulating hormones during childhood and the prenatal period, specifically focusing on ghrelin, leptin, peptide yy, glucagon-like-peptide 1 and pancreatic polypeptide.

This dissertation includes population-based research that was performed using the data of two Flemish cohorts, a birth cohort ENVIRONAGE (ENVIRonmental influence ON early AGEing) and a child/adolescent cohort IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS). In both cohorts data was collected on multiple exposures of the children and newborns. These exposures, could be combined by creating a multi-exposure score reflecting the exposome of the children, to assess the overall effect of a combination of exposures towards both outcomes, telomere attrition and appetite hormones.

The original research findings are presented in two parts (Part II–III). In Part II the relation between the exposome and telomere attrition is assessed in children (2–10 years old at baseline) (Chapter 1). Part III shifts focus to appetite regulation and its link to the exposome. Chapter 2 explores the relationship between the exposome and appetite-regulating hormones in children and adolescents (aged 4–16 years). Chapter 3 investigates the health relevance of appetite hormones in cord blood by examining their associations with early-life growth trajectories and body composition, key risk factors for later obesity. Chapter 4 assesses the influence of prenatal exposures on cord blood appetite hormone levels.

In summary, we observed that a combination of a healthy lifestyle and a green environment is associated with reduced telomere attrition over 5 to 7 years in childhood. Specifically, exposure to residential green space, particularly vegetation taller than 3 meters, was linked to slower telomere shortening, with part of this association mediated by smaller waist circumference. Environmental exposures at study (i.e. air pollution and residential green space), were also associated with fasting appetite hormone levels in children, potentially contributing to obesity development early in life. Similarly, prenatal exposure to air pollution was found to influence appetite hormone levels in cord blood. Interestingly, these cord blood appetite hormone levels were associated with postnatal growth trajectories and body composition. Collectively, these results highlight that the exposome influences internal processes related to biological ageing and appetite regulation as early as the prenatal and childhood periods.

This dissertation strengthens the existing literature on how lifestyle factors and environmental exposures are linked to biological processes, emphasizing that both lifestyle and environmental factors play critical roles in health starting from conception. It also provides new insights, particularly into the relationship between the exposome and appetite hormones early in life, and is the first to show associations between specific cord blood appetite hormones and postnatal growth and body composition. Therefore, this work can serve as a starting point for further exploration of appetite hormones, telomeres, and their potential contribution to the development of NCDs.

Future research should verify these results in other (larger) study populations, especially populations with a higher obesity prevalence and lower socio-economic status. Experimental studies are necessary to establish causality of the observed associations. Finally, methodological improvements are suggested to minimize bias.

From a public health perspective, this dissertation underscores the importance of early-life interventions targeting both lifestyle and environmental factors to reduce the risk of NCDs. By linking the exposome to biological ageing and appetite regulation, this work contributes to the growing body of evidence advocating for preventive strategies to address the NCD burden, particularly the obesity crisis, from an early age onwards. Ultimately, the research conducted in this dissertation emphasizes prevention as the cornerstone for sustainable health improvements, aligning with the adage: "Prevention is better than cure.